ORCID Profile
0000-0002-6385-0585
Current Organisation
Monash University
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Publisher: American Chemical Society (ACS)
Date: 15-02-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00047
Abstract: The adenosine A
Publisher: Wiley
Date: 21-06-2018
DOI: 10.1111/BPH.14337
Publisher: Springer Science and Business Media LLC
Date: 15-11-2018
DOI: 10.1038/S41598-018-35266-X
Abstract: Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A 1 receptor (A 1 AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A 1 AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A 1 AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A 1 AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist s led a significantly larger conformational space and even dissociated from the A 1 AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A 1 AR, which will greatly facilitate the receptor structure-based drug design.
Publisher: Springer Science and Business Media LLC
Date: 06-2018
DOI: 10.1038/S41586-018-0236-6
Abstract: The class A adenosine A
Publisher: American Chemical Society (ACS)
Date: 25-03-2010
DOI: 10.1021/NP900745G
Abstract: AMP-activated protein kinase (AMPK) has been proposed as a therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. The bioassay-guided fractionation of an EtOAc-soluble extract of the stem bark of Erythrina abyssinica led to the isolation of a new coumestan, erythribyssin N (1), and two new benzofurans, erythribyssin F (2) and erythribyssin H (3), along with five known compounds (4-8). When tested for their stimulatory effects on AMPK activity at a concentration of 10 muM, compounds 4 and 5 showed potent activation, while compounds 1, 2, and 7 had moderate effects. These results suggest that benzofurans and coumestans may be new lead compounds for regulating the AMPK enzyme.
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.BMC.2010.03.005
Abstract: During the course of a neuraminidase inhibitor screening program on natural products, four new (6, 8, 11, and 12) and eleven known (1-5, 7, 9-10, and 13-15) pterocarpan derivatives were isolated as active principles from the EtOAc extract of the stem bark of Erythrina abyssinica. Their structures were identified by spectroscopic data analyses. All isolates exhibited significant inhibitory effects on the neuraminidases from Clostridium perfringens and Vibrio cholerae with IC(50) values ranging from 1.32 to 77.10 microM and 0.35 to 77.73 microM, respectively. The isolates (1-3, 5-8, 10, and 13-15), which possessed noncompetitive inhibition modes in kinetic studies, showed stronger activity against C. perfringens neuraminidase (IC(50) 1.32-19.82 microM) than quercetin (IC(50) 25.34 microM), which was used as the positive control. In contrast, compounds 4 and 9 behaved as competitive inhibitors and were displayed less effective (IC(50) 26.39-33.55 microM). Furthermore, calopocarpine, as a neuraminidase inhibitor, produced a decrease of V. cholerae adhesion to the host cell. Overall, these results suggest that neuraminidase inhibitors can be used in the development of new treatments to combat infectious diseases.
Publisher: Elsevier BV
Date: 09-2023
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-05-2016
Publisher: Elsevier BV
Date: 2011
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.CELL.2017.01.042
Abstract: The adenosine A
Publisher: Cold Spring Harbor Laboratory
Date: 19-09-2023
Publisher: Frontiers Media SA
Date: 26-06-2023
DOI: 10.3389/FENDO.2023.1184360
Abstract: G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A 1 receptor (A 1 R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A 1 R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A 1 R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A 1 R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A 1 R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A 1 R as a potential therapeutic target and highlight recent advances in the structural understanding of A 1 R allosteric modulation.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 28-09-2016
Abstract: Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders however, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity, and efficacy. Docking and molecular dynamics (MD) simulations were performed using an A1AR homology model based on an agonist-bound A2AAR structure. Substitution of E172ECL2 for alanine reduced the affinity of the allosteric modulators PD81723 and VCP171 for the unoccupied A1AR. Residues involved in cooperativity with the orthosteric agonist NECA were different in PD81723 and VCP171 positive cooperativity between PD81723 and NECA was reduced on alanine substitution of a number of ECL2 residues, including E170ECL2 and K173ECL2, whereas mutation of W146ECL2 and W156ECL2 decreased VCP171 cooperativity with NECA. Molecular modeling localized a likely allosteric pocket for both modulators to an extracellular vestibule that overlaps with a region used by orthosteric ligands as they transit into the canonical A1AR orthosteric site. MD simulations confirmed a key interaction between E172ECL2 and both modulators. Bound PD81723 is flanked by another residue, E170ECL2, which forms hydrogen bonds with adjacent K168ECL2 and K173ECL2. Collectively, our data suggest E172ECL2 is a key allosteric ligand-binding determinant, whereas hydrogen-bonding networks within the extracellular vestibule may facilitate the transmission of cooperativity between orthosteric and allosteric sites.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 28-09-2016
Abstract: The adenosine A
Publisher: American Chemical Society (ACS)
Date: 16-03-2021
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.BCP.2017.11.016
Abstract: The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the α
Publisher: Wiley
Date: 16-06-2023
DOI: 10.1111/BPH.16099
Abstract: Heart failure remains a leading cause of morbidity and mortality worldwide. Current treatment for patients with heart failure include drugs targeting G protein‐coupled receptors such as β‐adrenoceptor antagonists (β‐blockers) and angiotensin II type 1 receptor antagonists (or angiotensin II receptor blockers). However, many patients progress to advanced heart failure with persistent symptoms, despite treatment with available therapeutics that have been shown to reduce mortality and mortality. GPCR targets currently being explored for the development of novel heart failure therapeutics include adenosine receptor, formyl peptide receptor, relaxin/insulin‐like family peptide receptor, vasopressin receptor, endothelin receptor and the glucagon‐like peptide 1 receptor. Many GPCR drug candidates are limited by insufficient efficacy and/or dose‐limiting unwanted effects. Understanding the current challenges hindering successful clinical translation and the potential to overcome existing limitations will facilitate the future development of novel heart failure therapeutics.
Publisher: Springer Science and Business Media LLC
Date: 08-09-2021
Publisher: Wiley
Date: 26-05-2023
DOI: 10.1111/BPH.16140
Abstract: The application of artificial intelligence (AI) approaches to drug discovery for G protein‐coupled receptors (GPCRs) is a rapidly expanding area. Artificial intelligence can be used at multiple stages during the drug discovery process, from aiding our understanding of the fundamental actions of GPCRs to the discovery of new ligand‐GPCR interactions or the prediction of clinical responses. Here, we provide an overview of the concepts behind artificial intelligence, including the subfields of machine learning and deep learning. We summarise the published applications of artificial intelligence to different stages of the GPCR drug discovery process. Finally, we reflect on the benefits and limitations of artificial intelligence and share our vision for the exciting potential for further development of applications to aid GPCR drug discovery. In addition to making the drug discovery process “faster, smarter and cheaper,” we anticipate that the application of artificial intelligence will create exciting new opportunities for GPCR drug discovery.
Publisher: American Chemical Society (ACS)
Date: 22-06-2022
Publisher: American Chemical Society (ACS)
Date: 13-12-2016
DOI: 10.1021/ACS.JMEDCHEM.6B01561
Abstract: The A
Start Date: 2021
End Date: End date not available
Funder: National Health and Medical Research Council
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