ORCID Profile
0000-0003-3119-6731
Current Organisation
Manipal Academy of Higher Education
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Biomechanics | Human Movement and Sports Science | Biomechanical Engineering |
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.BMCL.2008.06.045
Abstract: Facile synthesis of biaryl pyrazole sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716, 1) and an investigation of the effect of replacement of the -CO group in the compound 1 by the -SO(2) group in the aminopiperidine region is reported. Primary ex-vivo pharmacological testing and in vitro screening of sulfonamide derivative 2 showed the loss of CB1 receptor antagonism.
Publisher: Wiley
Date: 07-11-2022
Abstract: Infection of host cells by SARS‐CoV‐2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1‐RBD to undergo a conformational change into the ‘open’ conformation. These two events promote the binding of S1‐RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral‐cell membrane fusion. Combining ligand‐based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1‐RBD of SARS CoV‐2 and HS, revealing several low‐specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains. The evidence for multiple binding modes also suggest that highly specific inhibitors will not be optimal against protein S but, rather, erse HS‐based structures, characterized by high affinity and including multi‐valent compounds, may be required.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.DRUDIS.2010.10.009
Abstract: Glycosaminoglycans (GAGs) are an untapped source of novel chemical entities and, therefore, offer exciting new opportunities for the development of novel drug molecules because of their unique physical and biological properties. Advances in the functional understanding of GAG-protein interactions are enabling the development of GAG mimetics for use as anti-angiogenic, anti-metastatic, anti-inflammatory, anticoagulant and anti-thrombotic agents. Many anti-thrombotic molecules, such as Fondaparinux and Idraparinux, have been successful in clinical trials, and a new generation of heparin mimetic oligosaccharides and small molecules are currently in different stages of clinical development. In particular, the recent increased activity in the development of new mimetics by altering the composition of sulphated GAGs is very encouraging. This article reviews structurally defined heparin-mimetic oligosaccharides and small molecules currently in development or clinical trials.
Publisher: MDPI AG
Date: 24-02-2023
DOI: 10.3390/ANTIBIOTICS12030463
Abstract: Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using methods such as molecular docking. It would be of great interest to know in advance how well docking methods can reproduce the correct ligand binding modes and rank these correctly. We examined the performance of five molecular docking programs (AutoDock 4, AutoDock Vina, DOCK 6, rDock, and RLDock) for their ability to model ribosomal–ligand interactions with oxazolidinones. Eleven ribosomal crystal structures with oxazolidinones as the ligands were docked. The accuracy was evaluated by calculating the docked complexes’ root-mean-square deviation (RMSD) and the program’s internal scoring function. The rankings for each program based on the median RMSD between the native and predicted were DOCK 6 AD4 Vina RDOCK RLDOCK. Results demonstrate that the top-performing program, DOCK 6, could accurately replicate the ligand binding in only four of the eleven ribosomes due to the poor electron density of said ribosomal structures. In this study, we have further benchmarked the performance of the DOCK 6 docking algorithm and scoring in improving virtual screening (VS) enrichment using the dataset of 285 oxazolidinone derivatives against oxazolidinone binding sites in the S. aureus ribosome. However, there was no clear trend between the structure and activity of the oxazolidinones in VS. Overall, the docking performance indicates that the RNA pocket’s high flexibility does not allow for accurate docking prediction, highlighting the need to validate VS. protocols for ligand-RNA before future use. Later, we developed a re-scoring method incorporating absolute docking scores and molecular descriptors, and the results indicate that the descriptors greatly improve the correlation of docking scores and pMIC values. Morgan fingerprint analysis was also used, suggesting that DOCK 6 underpredicted molecules with tail modifications with acetamide, n-methylacetamide, or n-ethylacetamide and over-predicted molecule derivatives with methylamino bits. Alternatively, a ligand-based approach similar to a field template was taken, indicating that each derivative’s tail groups have strong positive and negative electrostatic potential contributing to microbial activity. These results indicate that one should perform VS. c aigns of ribosomal antibiotics with care and that more comprehensive strategies, including molecular dynamics simulations and relative free energy calculations, might be necessary in conjunction with VS. and docking.
Publisher: American Chemical Society (ACS)
Date: 23-11-2010
DOI: 10.1021/CI100321H
Abstract: The leucine zipper region of activator protein-1 (AP-1) comprises the c-Jun and c-Fos proteins and constitutes a well-known coiled coil protein-protein interaction motif. We have used molecular dynamics (MD) simulations in conjunction with the molecular mechanics/Poisson-Boltzmann generalized-Born surface area [MM/PB(GB)SA] methods to predict the free energy of interaction of these proteins. In particular, the influence of the choice of solvation model, protein force field, and water potential on the stability and dynamic properties of the c-Fos-c-Jun complex were investigated. Use of the AMBER polarizable force field ff02 in combination with the polarizable POL3 water potential was found to result in increased stability of the c-Fos-c-Jun complex. MM/PB(GB)SA calculations revealed that MD simulations using the POL3 water potential give the lowest predicted free energies of interaction compared to other nonpolarizable water potentials. In addition, the calculated absolute free energy of binding was predicted to be closest to the experimental value using the MM/GBSA method with independent MD simulation trajectories using the POL3 water potential and the polarizable ff02 force field, while all other binding affinities were overestimated.
Publisher: Elsevier BV
Date: 2021
Publisher: Wiley
Date: 14-06-2019
DOI: 10.1002/DDR.21557
Abstract: System x
Publisher: MDPI AG
Date: 22-07-2020
DOI: 10.3390/IJMS21155183
Abstract: A promising protein target for computational drug development, the human cluster of differentiation 38 (CD38), plays a crucial role in many physiological and pathological processes, primarily through the upstream regulation of factors that control cytoplasmic Ca2+ concentrations. Recently, a small-molecule inhibitor of CD38 was shown to slow down pathways relating to aging and DNA damage. We examined the performance of seven docking programs for their ability to model protein-ligand interactions with CD38. A test set of twelve CD38 crystal structures, containing crystallized biologically relevant substrates, were used to assess pose prediction. The rankings for each program based on the median RMSD between the native and predicted were Vina, AD4 PLANTS, Gold, Glide, Molegro rDock. Forty-two compounds with known affinities were docked to assess the accuracy of the programs at affinity/ranking predictions. The rankings based on scoring power were: Vina, PLANTS Glide, Gold Molegro AutoDock 4 rDock. Out of the top four performing programs, Glide had the only scoring function that did not appear to show bias towards overpredicting the affinity of the ligand-based on its size. Factors that affect the reliability of pose prediction and scoring are discussed. General limitations and known biases of scoring functions are examined, aided in part by using molecular fingerprints and Random Forest classifiers. This machine learning approach may be used to systematically diagnose molecular features that are correlated with poor scoring accuracy.
Publisher: Oxford University Press (OUP)
Date: 19-03-2020
Abstract: Collagen undergoes many types of post-translational modifications (PTMs), including intracellular modifications and extracellular modifications. Among these PTMs, glycosylation of hydroxylysine (Hyl) is the most complicated. Experimental studies demonstrated that this PTM ceases once the collagen triple helix is formed and that Hyl-O-glycosylation modulates collagen fibrillogenesis. However, the underlying atomic-level mechanisms of these phenomena remain unclear. In this study, we first adapted the force field parameters for O-linkages between Hyl and carbohydrates and then investigated the influence of Hyl-O-glycosylation on the structure of type I collagen molecule, by performing comprehensive molecular dynamic simulations in explicit solvent of collagen molecule segment with and without the glycosylation of Hyl. Data analysis demonstrated that (i) collagen triple helices remain in a triple-helical structure upon glycosylation of Hyl (ii) glycosylation of Hyl modulates the peptide backbone conformation and their solvation environment in the vicinity and (iii) the attached sugars are arranged such that their hydrophilic faces are well exposed to the solvent, while their hydrophobic faces point towards the hydrophobic portions of collagen. The adapted force field parameters for O-linkages between Hyl and carbohydrates will aid future computational studies on proteins with Hyl-O-glycosylation. In addition, this work, for the first time, presents the detailed effect of Hyl-O-glycosylation on the structure of human type I collagen at the atomic level, which may provide insights into the design and manufacture of collagenous biomaterials and the development of biomedical therapies for collagen-related diseases.
Publisher: Wiley
Date: 16-04-2015
Abstract: Post mortem biochemical staging of Alzheimer's disease is currently based on immunochemical analysis of brain slices with the AT8 antibody. The epitope of AT8 is described around the pSer202 Thr205 region of the hyperphosphorylated form of the neuronal protein tau. In this study, NMR spectroscopy was used to precisely map the AT8 epitope on phosphorylated tau, and derive its defining structural features by a combination of NMR analyses and molecular dynamics. A particular turn conformation is stabilized by a hydrogen bond of the phosphorylated Thr205 residue to the amide proton of Gly207, and is further stabilized by the two Arg residues opposing the pSer202 Thr205.
Publisher: Frontiers Media SA
Date: 26-08-2021
DOI: 10.3389/FGENE.2021.716236
Abstract: Hormone-dependent cancers (HDC) are among the leading causes of death worldwide among both men and women. Some of the established risk factors of HDC include unhealthy lifestyles, environmental factors, and genetic influences. Numerous studies have been conducted to understand gene–cancer associations. Transcriptome-wide association studies (TWAS) integrate data from genome-wide association studies (GWAS) and gene expression (expression quantitative trait loci – eQTL) to yield meaningful information on biological pathways associated with complex traits/diseases. Recently, TWAS have enabled the identification of novel associations between HDC risk and protein-coding genes. In the present study, we performed a TWAS analysis using the summary data-based Mendelian randomization (SMR)–heterogeneity in dependent instruments (HEIDI) method to identify microRNAs (miRNAs), a group of non-coding RNAs (ncRNAs) associated with HDC risk. We obtained eQTL and GWAS summary statistics from the ncRNA-eQTL database and the National Human Genome Research Institute–European Bioinformatics Institute (NHGRI-EBI) GWAS Catalog. We identified 13 TWAS-significant miRNAs at cis regions (±1 Mb) associated with HDC risk (two, five, one, two, and three miRNAs for prostate, breast, ovarian, colorectal, and endometrial cancers, respectively). Among them, eight novel miRNAs were recognized in HDC risk. Eight protein-coding genes targeted by TWAS-identified miRNAs ( SIRT1 , SOX4 , RUNX2 , FOXA1 , ABL2 , SUB1 , HNRNPH1 , and WAC ) are associated with HDC functions and signaling pathways. Overall, identifying risk-associated miRNAs across a group of related cancers may help to understand cancer biology and provide novel insights into cancer genetic mechanisms. This customized approach can be applied to identify significant miRNAs in any trait/disease of interest.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8CP05191G
Abstract: Collagen unfolding on gold nanoparticles, demonstrating the health risk of bare gold nanoparticles.
Publisher: American Chemical Society (ACS)
Date: 05-11-2020
Publisher: Frontiers Media SA
Date: 28-11-2019
Publisher: American Chemical Society (ACS)
Date: 04-2008
DOI: 10.1021/BI702455E
Abstract: Platelet endothelial cell adhesion molecule 1 (PECAM-1) has many functions, including its roles in leukocyte extravasation as part of the inflammatory response and in the maintenance of vascular integrity through its contribution to endothelial cell-cell adhesion. PECAM-1 has been shown to mediate cell-cell adhesion through homophilic binding events that involve interactions between domain 1 of PECAM-1 molecules on adjacent cells. However, various heterophilic ligands of PECAM-1 have also been proposed. The possible interaction of PECAM-1 with glycosaminoglycans (GAGs) is the focus of this study. The three-dimensional structure of the extracellular immunoglobulin (Ig) domains of PECAM-1 were constructed using homology modeling and threading methods. Potential heparin/heparan sulfate-binding sites were predicted on the basis of their amino acid consensus sequences and a comparison with known structures of sulfate-binding proteins. Heparin and other GAG fragments have been docked to investigate the structural determinants of their protein-binding specificity and selectivity. The modeling has predicted two regions in PECAM-1 that appear to bind heparin oligosaccharides. A high-affinity binding site was located in Ig domains 2 and 3, and evidence for a low-affinity site in Ig domains 5 and 6 was obtained. These GAG-binding regions were distinct from regions involved in PECAM-1 homophilic interactions.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.FOODCHEM.2019.125182
Abstract: Molecular dynamics simulation was performed on sugar profile and moisture content-based mixture systems of six Indian honey s les. Comparative studies were performed to understand the interactive effects of fructose, glucose, sucrose, maltose and water on crystallization. All simulations led to formation of stable crystal but with different interaction energies. Post-simulation analysis showed that Fructose:Glucose of 1.18 formed the most stable crystal with highest van der Waals and electrostatic interactions. The stability of crystal was further validated with least gyration radius (209 ± 1.81 nm
Publisher: American Chemical Society (ACS)
Date: 29-03-2022
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3PY00319A
Abstract: Poly(2- n -propyl-2-oxazine) is better solvated and shows higher backbone flexibility than its oxazoline analogue in dichloromethane, resulting in short distances between chain ends and ultimately increased cyclization efficiency.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2017
DOI: 10.1007/S10237-016-0870-6
Abstract: Collagen is an abundant structural biopolymer in mammal vertebrates, providing structural support as well as mechanical integrity for connective tissues such as bone, ligament, and tendon. The mechanical behaviours of these tissues are determined by the nanomechanics of their structures at different hierarchies and the role of collagen structures in the extracellular matrix. Some studies revealed that there is significant microstructural difference in the longitudinal direction of the collagen fibril, which challenges the conventional rod-like assumption prevalently adopted in the existing studies. Motivated by this discrepancy, in this study, we investigated the longitudinal heterogeneous nanomechanical properties of type I collagen molecule to probe the origin of the longitudinal heterogeneity of the collagen fibril at the molecular level. A full length type I collagen molecule structure was built based on the experimentally calibrated nanostructure. Then, a suitable strain rate was determined for stretching the three intact 'gap' regions and three intact 'overlap' regions of the collagen molecule. Further, the nanomechanical properties of the six collagen molecule segments were characterized by performing steered molecular dynamics simulations, using the obtained suitable strain rate in modelling. The results indicate that this computational model can be used to capture the mechanical behaviour of the collagen molecule under physiological stress conditions. Moreover, the 'gap' regions show a lower stiffness and undergo a slightly lager strain in the unwinding process, compared to the 'overlap' regions of the collagen molecule. This investigation provides insights into the origin of the longitudinal heterogeneity of collagen fibrils at the molecular level and suggests that it is of significant importance to consider the longitudinal heterogeneous mechanical properties of the collagen molecule in the development of coarse-grained models of collagen-related tissues.
Publisher: MDPI AG
Date: 20-09-2021
DOI: 10.20944/PREPRINTS202109.0337.V1
Abstract: The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that not only messenger RNAs but also other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other& rsquo s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long non-coding RNAs-associated ceRNA networks. Here, we identify an extended-ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of four hormone-dependent (HD) cancers, i.e., prostate, breast, colorectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across four HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding shared molecular pathogenesis in a group of related diseases.
Publisher: Wiley
Date: 14-02-2023
DOI: 10.1002/PRO.4572
Abstract: The anaphase‐promoting complex/cyclosome (APC/C) ubiquitin ligase and its cofactor, Cdh1, regulate the expression of several cell‐cycle proteins and their functions during mitosis. Levels of the protein cell ision cycle‐associated protein 3 (CDCA3), which is functionally required for mitotic entry, are regulated by APC/C Cdh1 . CDCA3 is an intrinsically disordered protein and contains both C‐terminal KEN box and D‐box recognition motifs, enabling binding to Cdh1. Our previous findings demonstrate that CDCA3 has a phosphorylation‐dependent non‐canonical ABBA‐like motif within the linker region bridging these two recognition motifs and is required for efficient binding to Cdh1. Here, we sought to identify and further characterize additional residues that participate within this ABBA‐like motif using detailed in vitro experiments and in silico modeling studies. We identified the role of H‐bonds, hydrophobic and ionic interactions across the CDCA3 ABBA‐like motif in the linker region between KEN and D‐box motifs. This linker region adopts a well‐defined structure when bound to Cdh1 in the presence of phosphorylation. Upon alanine mutation, the structure of this region is lost, leading to higher flexibility, and alteration in affinities due to binding to alternate sites on Cdh1. Our findings identify roles for the anchoring residues in the non‐canonical ABBA‐like motif to promote binding to the APC/C Cdh1 and regulation of CDCA3 protein levels.
Publisher: Public Library of Science (PLoS)
Date: 07-11-2008
Publisher: Wiley
Date: 13-08-2012
DOI: 10.1002/BIP.22099
Abstract: The c-Fos-c-Jun complex forms the activator protein 1 transcription factor, a therapeutic target in the treatment of cancer. Various synthetic peptides have been designed to try to selectively disrupt the interaction between c-Fos and c-Jun at its leucine zipper domain. To evaluate the binding affinity between these synthetic peptides and c-Fos, polarizable and nonpolarizable molecular dynamics (MD) simulations were conducted, and the resulting conformations were analyzed using the molecular mechanics generalized Born surface area (MM/GBSA) method to compute free energies of binding. In contrast to empirical and semiempirical approaches, the estimation of free energies of binding using a combination of MD simulations and the MM/GBSA approach takes into account dynamical properties such as conformational changes, as well as solvation effects and hydrophobic and hydrophilic interactions. The predicted binding affinities of the series of c-Jun-based peptides targeting the c-Fos peptide show good correlation with experimental melting temperatures. This provides the basis for the rational design of peptides based on internal, van der Waals, and electrostatic interactions.
Publisher: Springer New York
Date: 15-12-2017
DOI: 10.1007/978-1-4939-6598-4_3
Abstract: The Tau protein plays an important role due to its biomolecular interactions in neurodegenerative diseases. The lack of stable structure and various posttranslational modifications such as phosphorylation at various sites in the Tau protein pose a challenge for many experimental methods that are traditionally used to study protein folding and aggregation. Atomistic molecular dynamics (MD) simulations can help around deciphering relationship between phosphorylation and various intermediate and stable conformations of the Tau protein which occur on longer timescales. This chapter outlines protocols for the preparation, execution, and analysis of all-atom MD simulations of a 21-amino acid-long phosphorylated Tau peptide with the aim of generating biologically relevant structural and dynamic information. The simulations are done in explicit solvent and starting from nearly extended configurations of the peptide. The scaled MD method implemented in AMBER14 was chosen to achieve enhanced conformational s ling in addition to a conventional MD approach, thereby allowing the characterization of folding for such an intrinsically disordered peptide at 293 K. Emphasis is placed on the analysis of the simulation trajectories to establish correlations with NMR data (i.e., chemical shifts and NOEs). Finally, in-depth discussions are provided for commonly encountered problems.
Publisher: Wiley
Date: 19-06-2021
Abstract: Heparan sulfate (HS) is a complex, polyanionic polysaccharide ubiquitously expressed on cell surfaces and in the extracellular matrix. HS interacts with numerous proteins to mediate a vast array of biological and pathological processes. Inhibition of HS‐protein interactions is thus an attractive approach for new therapeutic development for cancer and infectious diseases, including COVID‐19 however, synthesis of well‐defined native HS oligosaccharides remains challenging. This has aroused significant interest in the development of HS mimetics which are more synthetically tractable and have fewer side effects, such as undesired anticoagulant activity. This account provides a perspective on the design and synthesis of different classes of HS mimetics with useful properties, and the development of various assays and molecular modelling tools to progress our understanding of their interactions with HS‐binding proteins.
Publisher: SAGE Publications
Date: 30-06-2015
Abstract: This study examines pregnancy and early infant outcomes of pregnant women with a clinical diagnosis of Borderline Personality Disorder presenting for obstetric services to a major metropolitan maternity hospital in Victoria, Australia. A retrospective case review of pregnancy and early infant outcomes on 42 women who had been diagnosed with Borderline Personality Disorder via psychiatric assessment using DSM-IV-R criteria was undertaken. Outcomes were compared with a control group of 14,313 consisting of women and infants of non-affected women from the same hospital over the same period of time. Women presenting for obstetric services with a clinical diagnosis of Borderline Personality Disorder experienced considerable psychosocial impairment. They anticipated birth as traumatic and frequently requested early delivery. High comorbidity with substance abuse was found and high rates of referral to child protective services. Mothers with Borderline Personality Disorder were significantly more likely to have negative birth outcomes such as lowered Apgar scores, prematurity and special care nursery referral when compared with controls. These findings offer preliminary evidence to be considered by clinicians in developing treatments and services for the perinatal care of women with Borderline Personality Disorder and their infants. Further research is required in order to develop evidence informed clinical guidelines for the management of women with Borderline Personality Disorder and their infants.
Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2020
DOI: 10.1101/2020.06.24.169334
Abstract: Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a co-receptor with the ACE2 protein for recognition of the S1 spike protein on SARS-CoV-2 virus, providing a tractable new target for therapeutic intervention. Clinically-used heparins demonstrate inhibitory activity, but world supplies are limited, necessitating alternative solutions. Synthetic HS mimetic pixatimod is a drug candidate for cancer with immunomodulatory and heparanase-inhibiting properties. Here we show that pixatimod binds to and destabilizes the SARS-CoV-2 spike protein receptor binding domain (S1-RBD), and directly inhibits its binding to human ACE2, consistent with molecular modelling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of live SARS-CoV-2 virus show that pixatimod potently inhibits infection of monkey Vero E6 and human bronchial epithelial cells at concentrations within its safe therapeutic dose range. Furthermore, in a K18-hACE2 mouse model pixatimod demonstrates that pixatimod markedly attenuates SARS-CoV-2 viral titer and COVID-19-like symptoms. This demonstration of potent anti-SARS-CoV-2 activity establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics. Together with other known activities of pixatimod our data provides a strong rationale for its clinical investigation as a potential multimodal therapeutic to address the COVID-19 pandemic.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1016/J.BMCL.2008.06.038
Abstract: Design and synthesis of a novel 3-hydroxy-cyclobut-3-ene-1,2-dione derivatives are reported and their in vitro thyroid hormone receptor selectivity has been evaluated in the thyroid luciferase receptor assay. The 3-[3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy)-phenylamino]-4-hydroxy-cyclobut-3-ene-1,2-dione 21 has shown selectivity towards thyroid hormone receptor beta.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0CP00268B
Abstract: Lung surfactant monolayer’s (acts as the first line barrier for inhaled nanoparticles) components (lipids and peptides) rearrange themselves by the influence of exposed gold nanoparticles at various stages of the breathing cycle.
Publisher: Bentham Science Publishers Ltd.
Date: 09-2008
Publisher: MDPI AG
Date: 07-06-2016
DOI: 10.3390/BIOM6020028
Abstract: In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked to both aspects. NMR spectroscopy has depicted accurate phosphorylation patterns by different kinases, and its non-destructive character has allowed functional assays with the same s les. Finally, we will discuss other post-translational modifications of Tau and its interaction with other cellular factors in relationship to its (dys)function.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2019
DOI: 10.1038/S41467-019-13167-5
Abstract: The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor–Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown. Here, we report that Banf1 controls the DNA damage response to oxidative stress via regulation of poly [ADP-ribose] polymerase 1 (PARP1). Specifically, oxidative lesions promote direct binding of Banf1 to PARP1, a critical NAD + -dependent DNA repair protein, leading to inhibition of PARP1 auto-ADP-ribosylation and defective repair of oxidative lesions, in cells with increased Banf1. Consistent with this, cells from patients with NGPS have defective PARP1 activity and impaired repair of oxidative lesions. These data support a model whereby Banf1 is crucial to reset oxidative-stress-induced PARP1 activity. Together, these data offer insight into Banf1-regulated, PARP1-directed repair of oxidative lesions.
Publisher: Elsevier BV
Date: 2021
Publisher: Frontiers Media SA
Date: 17-06-2021
DOI: 10.3389/FNMOL.2021.661368
Abstract: Phosphorylation of the neuronal microtubule-associated Tau protein plays a critical role in the aggregation process leading to the formation of insoluble intraneuronal fibrils within Alzheimer’s disease (AD) brains. In recent years, other posttranslational modifications (PTMs) have been highlighted in the regulation of Tau (dys)functions. Among these PTMs, the O -β-linked N-acetylglucosaminylation ( O -GlcNAcylation) modulates Tau phosphorylation and aggregation. We here focus on the role of the PHF-1 phospho-epitope of Tau C-terminal domain that is hyperphosphorylated in AD (at pS396 S404) and encompasses S400 as the major O -GlcNAc site of Tau while two additional O -GlcNAc sites were found in the extreme C-terminus at S412 and S413. Using high resolution NMR spectroscopy, we showed that the O -GlcNAc glycosylation reduces phosphorylation of PHF-1 epitope by GSK3β alone or after priming by CDK2/cyclin A. Furthermore, investigations of the impact of PTMs on local conformation performed in small peptides highlight the role of S404 phosphorylation in inducing helical propensity in the region downstream pS404 that is exacerbated by other phosphorylations of PHF-1 epitope at S396 and S400, or O -GlcNAcylation of S400. Finally, the role of phosphorylation and O -GlcNAcylation of PHF-1 epitope was probed in in-vitro fibrillization assays in which O -GlcNAcylation slows down the rate of fibrillar assembly while GSK3β phosphorylation stimulates aggregation counteracting the effect of glycosylation.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.BBAMEM.2019.06.001
Abstract: Inhaled nanoparticles (NPs) are experienced by the first biological barrier inside the alveolus known as lung surfactant (LS), a surface tension reducing agent, consisting of phospholipids and proteins in the form of the monolayer at the air-water interface. The monolayer surface tension is continuously regulated by the alveolus compression and expansion and protects the alveoli from collapsing. Inhaled NPs can reach deep into the lungs and interfere with the biophysical properties of the lung components. The interaction mechanisms of bare gold nanoparticles (AuNPs) with the LS monolayer and the consequences of the interactions on lung function are not well understood. Coarse-grained molecular dynamics simulations were carried out to elucidate the interactions of AuNPs with simplified LS monolayers at the nanoscale. It was observed that the interactions of AuNPs and LS components deform the monolayer structure, change the biophysical properties of LS and create pores in the monolayer, which all interfere with the normal lungs function. The results also indicate that AuNP concentrations >0.1 mol% (of AuNPs/lipids) hinder the lowering of the LS surface tension, a prerequisite of the normal breathing process. Overall, these findings could help to identify the possible consequences of airborne NPs inhalation and their contribution to the potential development of various lung diseases.
Publisher: Impact Journals, LLC
Date: 27-04-2018
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1038/S42003-021-02136-8
Abstract: Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell ision cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3 high tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3 low NSCLC tumours and benefit patients.
Publisher: Oxford University Press (OUP)
Date: 23-05-2014
Abstract: Glycosaminoglycans (GAGs) are complex polysaccharides involved in a wide range of biological signaling events, as well as being important as biological structural materials. Despite the ubiquity and importance of GAG-protein interactions in biological systems and potentially as therapeutic targets, detailed structures of such interactions are sparse in availability. Computational methods can provide detailed structural knowledge of these interactions however, they should be evaluated against suitable test systems prior to their widespread use. In this study, we have investigated the application of automated molecular docking and interaction mapping techniques to characterizing GAG-protein interactions. A series of high-resolution X-ray crystal structures of GAGs in complex with proteins was used to evaluate the approaches. Accurately scoring the pose fitting best with the crystal structure was a challenge for all docking programs evaluated. The site mapping technique offered excellent prediction of the key residues involved in ligand recognition, comparable to the best pose and improved over the top-ranked pose. A design protocol incorporating site- and ligand-based mapping techniques was developed and applied to identify GAGs capable of binding to acidic fibroblast growth factor (aFGF). The protocol was able to identify ligands known to bind to aFGF and accurately able to predict the binding modes of those ligands when using a known ligand-binding conformation of the protein. This study demonstrates the value of mapping-based techniques in identifying specific GAG epitopes recognized by proteins and for GAG-based drug design.
Publisher: Wiley
Date: 27-06-2022
DOI: 10.1002/JCB.30300
Abstract: Competing endogenous RNAs (ceRNAs) have become an emerging topic in cancer research due to their role in gene regulatory networks. To date, traditional ceRNA bioinformatic studies have investigated microRNAs as the only factor regulating gene expression. Growing evidence suggests that genomic (e.g., copy number alteration [CNA]), transcriptomic (e.g., transcription factors [TFs]), and epigenomic (e.g., DNA methylation [DM]) factors can influence ceRNA regulatory networks. Herein, we used the Least absolute shrinkage and selection operator regression, a machine learning approach, to integrate DM, CNA, and TFs data with RNA expression to infer ceRNA networks in cancer risk. The gene-regulating factors-mediated ceRNA networks were identified in four hormone-dependent (HD) cancer types: prostate, breast, colorectal, and endometrial. The shared ceRNAs across HD cancer types were further investigated using survival analysis, functional enrichment analysis, and protein-protein interaction network analysis. We found two (BUB1 and EXO1) and one (RRM2) survival-significant ceRNA(s) shared across breast-colorectal-endometrial and prostate-colorectal-endometrial combinations, respectively. Both BUB1 and BUB1B genes were identified as shared ceRNAs across more than two HD cancers of interest. These genes play a critical role in cell ision, spindle-assembly checkpoint signalling, and correct chromosome alignment. Furthermore, shared ceRNAs across multiple HD cancers have been involved in essential cancer pathways such as cell cycle, p53 signalling, and chromosome segregation. Identifying ceRNAs' roles across multiple related cancers will improve our understanding of their shared disease biology. Moreover, it contributes to the knowledge of RNA-mediated cancer pathogenesis.
Publisher: Springer Science and Business Media LLC
Date: 10-02-2023
DOI: 10.1038/S41598-023-29585-X
Abstract: Competing endogenous RNAs (ceRNAs) have gained attention in cancer research owing to their involvement in microRNA-mediated gene regulation. Previous studies have identified ceRNA networks of in idual cancers. Nevertheless, none of these studies has investigated different cancer stages. We identify stage-specific ceRNAs in breast cancer using the cancer genome atlas data. Moreover, we investigate the molecular functions and prognostic ability of ceRNAs involved in stage I–IV networks. We identified differentially expressed candidate ceRNAs using edgeR and limma R packages. A three-step analysis was used to identify statistically significant ceRNAs of each stage. Survival analysis and functional enrichment analysis were conducted to identify molecular functions and prognostic ability. We found five genes and one long non-coding RNA unique to the stage IV ceRNA network. These genes have been described in previous breast cancer studies. Genes acted as ceRNAs are enriched in cancer-associated pathways. Two, three, and three microRNAs from stages I, II, and III were prognostic from the Kaplan–Meier survival analysis. Our results reveal a set of unique ceRNAs in metastatic breast cancer. Further experimental work is required to evaluate their role in metastasis. Moreover, identifying stage-specific ceRNAs will improve the understanding of personalised therapeutics in breast cancer.
Publisher: Wiley
Date: 19-11-2008
DOI: 10.1111/J.1747-0285.2008.00741.X
Abstract: Glycosaminoglycans (GAGs) are important complex carbohydrates that participate in many biological processes through the regulation of their various protein partners. Biochemical, structural biology and molecular modelling approaches have assisted in understanding the molecular basis of such interactions, creating an opportunity to capitalize on the large structural ersity of GAGs in the discovery of new drugs. The complexity of GAG-protein interactions is in part due to the conformational flexibility and underlying sulphation patterns of GAGs, the role of metal ions and the effect of pH on the affinity of binding. Current understanding of the structure of GAGs and their interactions with proteins is here reviewed: the basic structures and functions of GAGs and their proteoglycans, their clinical significance, the three-dimensional features of GAGs, their interactions with proteins and the molecular modelling of heparin binding sites and GAG-protein interactions. This review focuses on some key aspects of GAG structure-function relationships using classical ex les that illustrate the specificity of GAG-protein interactions, such as growth factors, anti-thrombin, cytokines and cell adhesion molecules. New approaches to the development of GAG mimetics as possible new glycotherapeutics are also briefly covered.
Publisher: CRC Press
Date: 05-09-2012
DOI: 10.1201/B12965-16
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2RA01892F
Abstract: Molecular-level observations of the behavior of ligand functionalised gold nanoparticles with a lipid monolayers.
Publisher: American Chemical Society (ACS)
Date: 11-2007
DOI: 10.1021/JM061490U
Abstract: A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compounds--the bisulfate salt of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30--showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (+/-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.
Publisher: Wiley
Date: 31-01-2022
Abstract: Pixatimod (PG545), a heparan sulfate (HS) mimetic and anticancer agent currently in clinical trials, is a potent inhibitor of heparanase. Heparanase is an endo ‐β‐glucuronidase that degrades HS in the extracellular matrix and basement membranes and is implicated in numerous pathological processes such as cancer and viral infections, including SARS−CoV‐2. To understand how PG545 interacts with heparanase, we firstly carried out a conformational analysis through a combination of NMR experiments and molecular modelling which showed that the reducing end β‐D‐glucose residue of PG545 adopts a distorted conformation. This was followed by docking and molecular dynamics simulations to study the interactions of PG545 with heparanase, revealing that PG545 is able to block the active site by binding in different conformations, with the cholestanol side‐chain making important hydrophobic interactions. While PG545 blocks its natural substrate HS from binding to the active site, small synthetic heparanase substrates are only partially excluded, and thus pentasaccharide or larger substrates are preferred for assaying this class of inhibitor. This study provides new insights for the design of next‐generation heparanase inhibitors and substrates.
Publisher: American Chemical Society (ACS)
Date: 12-05-2020
DOI: 10.26434/CHEMRXIV.12279251.V1
Abstract: Glycosaminoglycans (GAGs) are a family of anionic carbohydrates that play an essential role in the physiology and pathology of all eukaryotic life. Experimental determination of GAG-protein complexes remains difficult due to the considerable ersity in both carbohydrate linkage, and sulfation patterns. To complement existing methods of structural determination, we present our molecular docking tool, GlycoTorchVina (GTV), which demonstrates a substantial improvement at reproducing low energy conformations of GAGs compared with traditional docking programs. Based on the carbohydrate specific docking program VinaCarb (VC), GTV utilizes rotational energy functions, calculated using density functional theory (DFT), specifically designed for glycosidic linkages found in GAGs. The redocking accuracy of four programs (GTV, VC, AutoDock Vina and Glide) was tested over a set of 10 high-quality crystal structures containing co-crystallized GAGs (tetrasaccharides or longer). GTV outperformed other programs and was able to reproduce the native pose of eight structures and produced top-scoring docked poses that were on average only 1.8 Å RMSD away from the crystal structure. Although imitation of crystal structures is a standard test used for assessing the accuracy of docking programs, we illustrate how the underlying quality of the crystal structure, which is often overlooked during benchmarking, affects conclusions drawn from this approach. Statistical and theoretical investigations into charge-charge (“salt-bridge”) interactions are also presented. Again, DFT calculations were used to derive non-bonded potentials describing salt-bridges, and solvent-mediated charge-charge (“water-bridge”) interactions. These data suggest that water-bridges play an important, yet poorly understood, role in the structures of GAG-protein complexes.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2019
DOI: 10.1557/ADV.2019.93
Publisher: Cold Spring Harbor Laboratory
Date: 31-08-2023
Publisher: Oxford University Press (OUP)
Date: 11-07-2012
Abstract: Mammalian heparanase is an endo-β-glucuronidase associated with cell invasion in cancer metastasis, angiogenesis and inflammation. Heparanase cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, releasing heparin/heparan sulfate oligosaccharides of appreciable size. This in turn causes the release of growth factors, which accelerate tumor growth and metastasis. Heparanase has two glycosaminoglycan-binding domains however, no three-dimensional structure information is available for human heparanase that can provide insights into how the two domains interact to degrade heparin fragments. We have constructed a new homology model of heparanase that takes into account the most recent structural and bioinformatics data available. Heparin analogs and glycosaminoglycan mimetics were computationally docked into the active site with energetically stable ring conformations and their interaction energies were compared. The resulting docked structures were used to propose a model for substrates and conformer selectivity based on the dimensions of the active site. The docking of substrates and inhibitors indicates the existence of a large binding site extending at least two saccharide units beyond the cleavage site (toward the nonreducing end) and at least three saccharides toward the reducing end (toward heparin-binding site 2). The docking of substrates suggests that heparanase recognizes the N-sulfated and O-sulfated glucosamines at subsite +1 and glucuronic acid at the cleavage site, whereas in the absence of 6-O-sulfation in glucosamine, glucuronic acid is docked at subsite +2. These findings will help us to focus on the rational design of heparanase-inhibiting molecules for anticancer drug development by targeting the two heparin/heparan sulfate recognition domains.
Publisher: Wiley
Date: 24-03-2014
DOI: 10.1002/PROT.24544
Abstract: Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau225-250) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal β-sheet pattern (226VAVVR230 and 244QTAPVP249), replacing it with a range of structures. The double pThr231 Ser235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structural characterization, with the observation of a transient α-helix (239AKSRLQT245). PPII helical conformations were only found sporadically throughout the simulations.
Publisher: MDPI AG
Date: 09-10-2021
Abstract: The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that messenger RNAs and other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other’s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long-non-coding RNA-associated ceRNA networks. Here, we identify an extended ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of five hormone-dependent (HD) cancers, i.e., prostate, breast, colon, rectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across five HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene-associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding the shared molecular pathogenesis in a group of related diseases.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Wiley
Date: 20-10-2023
DOI: 10.1002/PROT.26604
Publisher: CRC Press
Date: 27-09-2012
DOI: 10.1201/B12965
Publisher: MDPI AG
Date: 06-03-2019
DOI: 10.3390/MOLECULES24050924
Abstract: Glycosaminoglycan (GAG) mimetics are synthetic or semi-synthetic analogues of heparin or heparan sulfate, which are designed to interact with GAG binding sites on proteins. The preclinical stages of drug development rely on efficacy and toxicity assessment in animals and aim to apply these findings to clinical studies. However, such data may not always reflect the human situation possibly because the GAG binding site on the protein ligand in animals and humans could differ. Possible inter-species differences in the GAG-binding sites on antithrombin III, heparanase, and chemokines of the CCL and CXCL families were examined by sequence alignments, molecular modelling and assessment of surface electrostatic potentials to determine if one species of laboratory animal is likely to result in more clinically relevant data than another. For each protein, current understanding of GAG binding is reviewed from a protein structure and function perspective. This combinatorial analysis shows chemokine dimers and oligomers can present different GAG binding surfaces for the same target protein, whereas a cleft-like GAG binding site will differently influence the types of GAG structures that bind and the species preferable for preclinical work. Such analyses will allow an informed choice of animal(s) for preclinical studies of GAG mimetic drugs.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2021
DOI: 10.1038/S42003-021-01998-2
Abstract: Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.JMGM.2011.11.001
Abstract: Genetic engineering of Bacillus thuringiensis (Bt) Cry proteins has resulted in the synthesis of various novel toxin proteins with enhanced insecticidal activity and specificity towards different insect pests. In this study, a fusion protein consisting of the DI-DII domains of Cry1Ac and garlic lectin (ASAL) has been designed in silico by replacing the DIII domain of Cry1Ac with ASAL. The binding interface between the DI-DII domains of Cry1Ac and lectin has been identified using protein-protein docking studies. Free energy of binding calculations and interaction profiles between the Cry1Ac and lectin domains confirmed the stability of fusion protein. A total of 18 hydrogen bonds was observed in the DI-DII-lectin fusion protein compared to 11 hydrogen bonds in the Cry1Ac (DI-DII-DIII) protein. Molecular mechanics/Poisson-Boltzmann (generalized-Born) surface area [MM/PB (GB) SA] methods were used for predicting free energy of interactions of the fusion proteins. Protein-protein docking studies based on the number of hydrogen bonds, hydrophobic interactions, aromatic-aromatic, aromatic-sulphur, cation-pi interactions and binding energy of Cry1Ac/fusion proteins with the aminopeptidase N (APN) of Manduca sexta rationalised the higher binding affinity of the fusion protein with the APN receptor compared to that of the Cry1Ac-APN complex, as predicted by ZDOCK, Rosetta and ClusPro analysis. The molecular binding interface between the fusion protein and the APN receptor is well packed, analogously to that of the Cry1Ac-APN complex. These findings offer scope for the design and development of customized fusion molecules for improved pest management in crop plants.
Publisher: American Chemical Society (ACS)
Date: 02-02-2021
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JMBBM.2018.07.009
Abstract: Collagen is a common structural protein, providing mechanical integrity for various vertebrate connective tissues such as cartilage and bone. The mechanical behaviours of these tissues under physical stimulations are controlled by the hierarchical structure of collagen and its interactions with other extracellular matrix molecules. However, the mechanical properties and deformation mechanisms of natural collagen under physiological loading rates at the molecular level are not fully understood. In this study, comprehensive steered molecular dynamics (SMD) simulations were performed on the 2nd intact overlap region (d2ol) and the 2nd intact D-period (d2olgp) of an in-situ characterized collagen molecule, under a large range of strain rates (6.5 × 10
Publisher: American Chemical Society (ACS)
Date: 12-05-2020
DOI: 10.26434/CHEMRXIV.12279251
Abstract: Glycosaminoglycans (GAGs) are a family of anionic carbohydrates that play an essential role in the physiology and pathology of all eukaryotic life. Experimental determination of GAG-protein complexes remains difficult due to the considerable ersity in both carbohydrate linkage, and sulfation patterns. To complement existing methods of structural determination, we present our molecular docking tool, GlycoTorchVina (GTV), which demonstrates a substantial improvement at reproducing low energy conformations of GAGs compared with traditional docking programs. Based on the carbohydrate specific docking program VinaCarb (VC), GTV utilizes rotational energy functions, calculated using density functional theory (DFT), specifically designed for glycosidic linkages found in GAGs. The redocking accuracy of four programs (GTV, VC, AutoDock Vina and Glide) was tested over a set of 10 high-quality crystal structures containing co-crystallized GAGs (tetrasaccharides or longer). GTV outperformed other programs and was able to reproduce the native pose of eight structures and produced top-scoring docked poses that were on average only 1.8 Å RMSD away from the crystal structure. Although imitation of crystal structures is a standard test used for assessing the accuracy of docking programs, we illustrate how the underlying quality of the crystal structure, which is often overlooked during benchmarking, affects conclusions drawn from this approach. Statistical and theoretical investigations into charge-charge (“salt-bridge”) interactions are also presented. Again, DFT calculations were used to derive non-bonded potentials describing salt-bridges, and solvent-mediated charge-charge (“water-bridge”) interactions. These data suggest that water-bridges play an important, yet poorly understood, role in the structures of GAG-protein complexes.
Publisher: MDPI AG
Date: 23-08-2017
DOI: 10.3390/IJMS18091832
Publisher: MDPI AG
Date: 28-08-2021
DOI: 10.3390/IJMS22179354
Abstract: SOX2 is an oncogenic transcription factor overexpressed in nearly half of the basal-like triple-negative breast cancers associated with very poor outcomes. Targeting and inhibiting SOX2 is clinically relevant as high SOX2 mRNA levels are positively correlated with decreased overall survival and progression-free survival in patients affected with breast cancer. Given its key role as a master regulator of cell proliferation, SOX2 represents an important scaffold for the engineering of dominant-negative synthetic DNA-binding domains (DBDs) that act by blocking or interfering with the oncogenic activity of the endogenous transcription factor in cancer cells. We have synthesized an interference peptide (iPep) encompassing a truncated 24 amino acid long C-terminus of SOX2 containing a potential SOX-specific nuclear localization sequence, and the determinants of the binding of SOX2 to the DNA and to its transcription factor binding partners. We found that the resulting peptide (SOX2-iPep) possessed intrinsic cell penetration and promising nuclear localization into breast cancer cells, and decreased cellular proliferation of SOX2 overexpressing cell lines. The novel SOX2-iPep was found to exhibit a random coil conformation predominantly in solution. Molecular dynamics simulations were used to characterize the interactions of both the SOX2 transcription factor and the SOX2-iPep with FGF4-enhancer DNA in the presence of the POU domain of the partner transcription factor OCT4. Predictions of the free energy of binding revealed that the iPep largely retained the binding affinity for DNA of parental SOX2. This work will enable the future engineering of novel dominant interference peptides to transport different therapeutic cargo molecules such as anti-cancer drugs into cells.
Publisher: Elsevier BV
Date: 07-2006
DOI: 10.1016/J.BMCL.2006.04.023
Abstract: Three-dimensional QSAR studies for N-4-arylacryloylpiperazin-1-yl-phenyl-oxazolidinones were conducted using TSAR 3.3. The in vitro activities (MICs) of the compounds against Staphylococcus aureus ATCC 25923 exhibited a strong correlation with the prediction made by the model developed in the present study.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.ANTIVIRAL.2019.05.004
Abstract: Dengue virus (DENV) is the most prevalent mosquito-borne flavivirus that infects humans. At present, there are no specific antiviral drugs to treat DENV infection and vaccine development has met with challenges. DENV encodes two glycosaminoglycan (GAG) binding proteins Envelope (E) and non-structural protein 1 (NS1). While previous work has validated the use of GAG analogues as inhibitors of E mediated virus-cell attachment, their potential for antiviral intervention in NS1 protein toxicity has not yet been explored. Here, we investigate the potential of the heparan sulfate mimetic PG545 as a dual purpose compound to target both DENV virion infectivity and NS1 function. In comparison to a non-sulfated analogue, we show that PG545 potently inhibits DENV infectivity with no cytotoxic effect. Against NS1, PG545 completely blocks the induction of cellular activation and abolishes NS1-mediated disruption of endothelial monolayer integrity. Furthermore, PG545 treatment moderately improves survival from lethal DENV challenge in a murine model. At peak disease, PG545-treated mice have lower viremia, circulating NS1 and serum TNF-α. Consistent with anti-NS1 activity, PG545 treatment also reduces systemic vascular leakage caused by DENV infection in vivo. Taken together, these findings demonstrate that the dual targeting of DENV virions and NS1 using GAG analogues offers a new avenue for DENV drug development.
Publisher: American Chemical Society (ACS)
Date: 07-02-2011
DOI: 10.1021/CI1003366
Abstract: CXCL-8 (Interleukin 8) is a CXC chemokine with a central role in the human immune response. We have undertaken extensive in silico analyses to elucidate the interactions of CXCL-8 with its various binding partners, which are crucial for its biological function. Sequence and structure analyses showed that residues in the thirdq β-sheet and basic residues in the heparin binding site are highly variable, while residues in the second β-sheet are highly conserved. Molecular dynamics simulations in aqueous solution of dimeric CXCL-8 have been performed with starting geometries from both X-ray and NMR structures showed shearing movements between the two antiparallel C-terminal helices. Dynamic conservation analyses of these simulations agreed with experimental data indicating that structural differences between the two structures at quaternary level arise from changes in the secondary structure of the N-terminal loop, the 3(10)-helix, the 30s, 40s, and 50s loops and the third β-sheet, resulting in a different interhelical separation. Nevertheless, the observation of these different states indicates that CXCL-8 has the potential to undergo conformational changes, and it seems likely that this feature is relevant to the mode of binding of glycosaminoglycan (GAG) mimetics such as cyclitols. Simulations of the receptor peptide fragment-CXCL-8 complex identified several specific interactions of the receptor peptide with CXCL-8 that could be exploited in the structure-based design of competitive peptides and nonpeptidic molecules targeting CXCL-8 for combating inflammatory diseases. Simulations of the CXCL-8 dimer complexed with a 24-mer heparin fragment and of the CXCL-8-receptor peptide complex revealed that Arg60, Lys64, and Arg68 in the dimer bind to cyclitols in a horseshoe pattern, defining a region which is spatially distinct from the receptor binding site. There appears to be an optimum number of sulfates and an optimum length of alkyl spacers required for the interaction of cyclitol inhibitors with the dimeric form of CXCL-8. Calculation of the binding affinities of cyclitol inhibitors reflected satisfactorily the ranking of experimentally determined inhibitory potencies. The findings of these molecular modeling studies will help in the search for inhibitors which can modulate various CXCL-8 biological activities and serve as an excellent model system to study CXC-inhibitor interactions.
Publisher: Oxford University Press (OUP)
Date: 30-07-2009
Abstract: Glycosaminoglycans (GAGs) are complex highly charged linear polysaccharides that have a variety of roles in biological processes. We report the first use of molecular dynamics (MD) free energy calculations using the MM/PBSA method to investigate the binding of GAGs to protein molecules, namely the platelet endothelial cell adhesion molecule 1 (PECAM-1) and annexin A2. Calculations of the free energy of the binding of heparin fragments of different sizes reveal the existence of a region of low GAG-binding affinity in domains 5-6 of PECAM-1 and a region of high affinity in domains 2-3, consistent with experimental data and ligand-protein docking studies. A conformational hinge movement between domains 2 and 3 was observed, which allows the binding of heparin fragments of increasing size (pentasaccharides to octasaccharides) with an increasingly higher binding affinity. Similar simulations of the binding of a heparin fragment to annexin A2 reveal the optimization of electrostatic and hydrogen bonding interactions with the protein and protein-bound calcium ions. In general, these free energy calculations reveal that the binding of heparin to protein surfaces is dominated by strong electrostatic interactions for longer fragments, with equally important contributions from van der Waals interactions and vibrational entropy changes, against a large unfavorable desolvation penalty due to the high charge density of these molecules.
Publisher: American Chemical Society (ACS)
Date: 13-03-2019
DOI: 10.1021/ACS.LANGMUIR.8B03680
Abstract: The molecular behavior of proteins in the presence of inorganic surfaces is of fundamental biological significance. Ex les include extracellular matrix proteins interacting with gold nanoparticles and metallic implant biomaterials, such as titanium and stainless steels. Uncharged inorganic surfaces that interact strongly with the solution phase (hydrophilic surfaces) have been commonly used in disease treatments. A deep understanding of the molecular behavior of body proteins in the presence of hydrophilic surfaces is important in terms of clinical applications. However, the adsorption mechanism of proteins onto hydrophilic surfaces remains not fully understood. Here, comprehensive molecular dynamics simulations are carried out to study the molecular response of a human collagen molecule segment (CMS) to the presence of a planar gold surface (AuNS) in explicit solvent, aiming to unravel the adsorption mechanism of proteins onto hydrophilic surfaces. The results demonstrate that in the presence of AuNS, the CMS first biasedly diffuses toward AuNS, followed by anchoring to the gold surface, and finally adsorbs stepwise onto AuNS, where the protein adjusts its structure to maximize the interaction with AuNS. We conclude that adsorption of proteins onto hydrophilic surfaces adheres to three steps, namely, biased diffusion, anchoring, and stepwise adsorption accompanied by structural adaptation. The obtained adsorption mechanism provides insights into the development of inorganic surfaces for biomedical and therapeutic applications.
Publisher: Georg Thieme Verlag KG
Date: 12-2020
Abstract: The dependence of development and homeostasis in animals on the interaction of hundreds of extracellular regulatory proteins with the peri- and extracellular glycosaminoglycan heparan sulfate (HS) is exploited by many microbial pathogens as a means of adherence and invasion. Heparin, a widely used anticoagulant drug, is structurally similar to HS and is a common experimental proxy. Exogenous heparin prevents infection by a range of viruses, including S-associated coronavirus isolate HSR1. Here, we show that heparin inhibits severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invasion of Vero cells by up to 80% at doses achievable through prophylaxis and, particularly relevant, within the range deliverable by nebulisation. Surface plasmon resonance and circular dichroism spectroscopy demonstrate that heparin and enoxaparin, a low-molecular-weight heparin which is a clinical anticoagulant, bind and induce a conformational change in the spike (S1) protein receptor-binding domain (S1 RBD) of SARS-CoV-2. A library of heparin derivatives and size-defined fragments were used to probe the structural basis of this interaction. Binding to the RBD is more strongly dependent on the presence of 2-O or 6-O sulfate groups than on N-sulfation and a hexasaccharide is the minimum size required for secondary structural changes to be induced in the RBD. It is likely that inhibition of viral infection arises from an overlap between the binding sites of heparin/HS on S1 RBD and that of the angiotensin-converting enzyme 2. The results suggest a route for the rapid development of a first-line therapeutic by repurposing heparin and its derivatives as antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.CARRES.2009.12.020
Abstract: The monosaccharide 2-O-sulfo-alpha-L-iduronic acid (IdoA2S) is one of the major components of glycosaminoglycans. The ability of molecular mechanics force fields to reproduce ring-puckering conformational equilibrium is important for the successful prediction of the free energies of interaction of these carbohydrates with proteins. Here we report unconstrained molecular dynamics simulations of IdoA2S monosaccharide that were carried out to investigate the ability of commonly used force fields to reproduce its ring conformational flexibility in aqueous solution. In particular, the distribution of ring conformer populations of IdoA2S was determined. The GROMOS96 force field with the SPC/E water potential can predict successfully the dominant skew-boat to chair conformational transition of the IdoA2S monosaccharide in aqueous solution. On the other hand, the GLYCAM06 force field with the TIP3P water potential s led transitional conformations between the boat and chair forms. Simulations using the GROMOS96 force field showed no pseudorotational equilibrium fluctuations and hence no inter-conversion between the boat and twist boat ring conformers. Calculations of theoretical proton NMR coupling constants showed that the GROMOS96 force field can predict the skew-boat to chair conformational ratio in good agreement with the experiment, whereas GLYCAM06 shows worse agreement. The omega rotamer distribution about the C5-C6 bond was predicted by both force fields to have torsions around 10 degrees , 190 degrees , and 360 degrees .
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.BIOCHI.2019.07.007
Abstract: Serum- and glucocorticoid-inducible kinase 1 (SGK1), a protein kinase, shares significant structural similarity with other members of the AGC protein kinase family. It has been reported that the inactive SGK1 structure lacks αC helix and this unique feature makes it distinct from other protein kinases. Activation of SGK1 by PDK1 requires phosphorylation at Thr256, but the structural insights of the activation remain unclear. The co-crystal structures of small molecule inhibitors, Magnesium (Mg
Publisher: Elsevier BV
Date: 12-2012
DOI: 10.1016/J.BBAPAP.2012.07.002
Abstract: Heparin is a glycosaminoglycan known to bind bone morphogenetic proteins (BMPs) and the growth and differentiation factors (GDFs) and has strong and variable effects on BMP osteogenic activity. In this paper we report our predictions of the likely heparin binding sites for BMP-2 and 14. The N-terminal sequences upstream of TGF-β-type cysteine-knot domains in BMP-2, 7 and 14 contain the basic residues arginine and lysine, which are key components of the heparin/HS-binding sites, with these residues being highly non-conserved. Importantly, evolutionary conserved surfaces on the beta sheets are required for interactions with receptors and antagonists. Furthermore, BMP-2 has electropositive surfaces on two sides compared to BMP-7 and BMP-14. Molecular docking simulations suggest the presence of high and low affinity binding sites in dimeric BMP-2. Histidines were found to play a role in the interactions of BMP-2 with heparin however, a pK(a) analysis suggests that histidines are likely not protonated. This is indicative that interactions of BMP-2 with heparin do not require acidic pH. Taken together, non-conserved amino acid residues in the N-terminus and residues protruding from the beta sheet (not overlapping with the receptor binding sites and the dimeric interface) and not C-terminal are found to be important for heparin-BMP interactions.
Publisher: American Chemical Society (ACS)
Date: 08-03-2008
DOI: 10.1021/BI7024595
Abstract: Platelet endothelial cell adhesion molecule 1 (PECAM-1) (CD31), a member of the immunoglobulin (Ig) superfamily of cell adhesion molecules with six Ig-like domains, has a range of functions, notably its contributions to leukocyte extravasation during inflammation and in maintaining vascular endothelial integrity. Although PECAM-1 is known to mediate cell adhesion by homophilic binding via domain 1, a number of PECAM-1 heterophilic ligands have been proposed. Here, the possibility that heparin and heparan sulfate (HS) are ligands for PECAM-1 was reinvestigated. The extracellular domain of PECAM-1 was expressed first as a fusion protein with the Fc region of human IgG1 fused to domain 6 and second with an N-terminal Flag tag on domain 1 (Flag-PECAM-1). Both proteins bound heparin immobilized on a biosensor chip in surface plasmon resonance (SPR) binding experiments. Binding was pH-sensitive but is easily measured at slightly acidic pH. A series of PECAM-1 domain deletions, prepared in both expression systems, were tested for heparin binding. This revealed that the main heparin-binding site required both domains 2 and 3. Flag-PECAM-1 and a Flag protein containing domains 1-3 bound HS on melanoma cell surfaces, but a Flag protein containing domains 1-2 did not. Heparin oligosaccharides inhibited Flag-PECAM-1 from binding immobilized heparin, with certain structures having greater inhibitory activity than others. Molecular modeling similarly identified the junction of domains 2 and 3 as the heparin-binding site and further revealed the importance of the iduronic acid conformation for binding. PECAM-1 does bind heparin/HS but by a site that is distinct from that required for homophilic binding.
Publisher: American Chemical Society (ACS)
Date: 18-03-2016
Abstract: The adsorption of proteins at the interface between two immiscible electrolyte solutions has been found to be key to their bioelectroactivity at such interfaces. Combined with interfacial complexation of organic phase anions by cationic proteins, this adsorption process may be exploited to achieve nanomolar protein detection. In this study, replica exchange molecular dynamics simulations have been performed to elucidate for the first time the molecular mechanism of adsorption and subsequent unfolding of hen egg white lysozyme at low pH at a polarized 1,2-dichloroethane/water interface. The unfolding of lysozyme was observed to occur as soon as it reaches the organic-aqueous interface, which resulted in a number of distinct orientations at the interface. In all cases, lysozyme interacted with the organic phase through regions rich in nonpolar amino acids, such that the side chains are directed toward the organic phase, whereas charged and polar residues were oriented toward the aqueous phase. By contrast, as expected, lysozyme in neat water at low pH does not exhibit significant structural changes. These findings demonstrate the key influence of the organic phase upon adsorption of lysozyme under the influence of an electric field, which results in the unfolding of its structure.
Start Date: 2019
End Date: 2022
Funder: Advance Queensland
View Funded ActivityStart Date: 2016
End Date: 2019
Funder: Queensland University of Technology
View Funded ActivityStart Date: 2012
End Date: 2016
Funder: Curtin University of Technology
View Funded ActivityStart Date: 2020
End Date: 2024
Funder: Australian Research Council
View Funded ActivityStart Date: 08-2020
End Date: 08-2025
Amount: $3,998,796.00
Funder: Australian Research Council
View Funded Activity