ORCID Profile
0000-0002-9086-8983
Current Organisations
National Research Centre
,
University of Western Australia
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Publisher: Informa UK Limited
Date: 08-06-2022
DOI: 10.1080/07391102.2022.2082533
Abstract: In this article, we describe a set of subsequent five-steps chemical reactions to synthesize a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (
Publisher: Elsevier BV
Date: 02-2019
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7RA04435F
Abstract: Fluorescence quenching of the anticancer AG1478, by at least three explicit water molecules, can be exploited to probe drug–protein binding interactions.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0NJ02844D
Abstract: Form B of mebendazole is the form expected to bind more efficiently with the colchicine binding site within the tubulin protein.
Publisher: Frontiers Media SA
Date: 24-03-2021
DOI: 10.3389/FCHEM.2021.628398
Abstract: Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole & Oxfendazole & Nocodazole & Mebendazole & Albendazole & Oxibendazole & Fenbendazole & Ciclobendazole & Thiabendazole & Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate.
Publisher: MDPI AG
Date: 13-10-2022
Abstract: In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.
Publisher: MDPI AG
Date: 21-06-2021
DOI: 10.3390/MOLECULES26123772
Abstract: The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure–activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.EJMECH.2018.01.072
Abstract: Recently a dramatic development of the cancer drug discovery has been shown in the field of targeted cancer therapy. Checkpoint kinase 2 (Chk2) inhibitors offer a promising approach to enhance the effectiveness of cancer chemotherapy. Accordingly, in this study many pyrimidine-benzimidazole conjugates were designed and twelve feasible derivatives were selected to be synthesized to investigate their activity against Chk2 and subjected to study their antitumor activity alone and in combination with the genotoxic anticancer drugs cisplatin and doxorubicin on breast carcinoma, (ER+) cell line (MCF-7). The results indicated that the studied compounds inhibited Chk2 activity with high potency (IC
Publisher: Elsevier BV
Date: 2024
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.SAA.2016.07.027
Abstract: We studied the spectroscopic characteristics of SKF86002, an anti-inflammatory and tyrosine kinase inhibitor drug candidate. Two conformers SKF86002A and SKF86002B are separated by energy barriers of 19.68kJ·mol(-1) and 6.65kJ·mol(-1) due to H-bonds, and produce the three major UV-Vis absorption bands at 325nm, 260nm and 210nm in cyclohexane solutions. This environment-sensitive fluorophore exhibited emission in the 400-500nm range with a marked response to changes in environment polarity. By using twenty-two solvents for the solvatochromism study, it was noticed that solvent polarity, represented by dielectric constant, was well correlated with the emission wavelength maxima of SKF86002. Thus, the SKF86002 fluorescence peak red shifted in aprotic solvents from 397.5nm in cyclohexane to 436nm in DMSO. While the emission maximum in hydrogen donating solvents ranged from 420nm in t-butanol to 446nm in N-methylformamide. Employing Lippert-Mataga, Bakhshiev and Kawski models, we found that one linear correlation provided a satisfactory description of polarity effect of 18 solvents on the spectral changes of SKF86002 with R(2) values 0.78, 0.80 and 0.80, respectively. Additionally, the multicomponent linear regression analysis of Kamlet-Taft (R(2)=0.94) revealed that solvent acidity, basicity and polarity accounted for 31%, 24% and 45% of solvent effects on SKF86002 emission, respectively. While Catalán correlation (R(2)=0.92) revealed that solvatochromic change of SKF86002 emission was attributed to changes in solvent dipolarity (71%), solvent polarity (12%), solvent acidity (11%) and solvent basicity (6%). Plot of Reichardt transition energies and emission energies of SKF86002 in 18 solvents showed also a linear correlation with R(2)=0.90. The dipole moment difference between excited and ground state was calculated to be 3.4-3.5debye.
Publisher: American Chemical Society (ACS)
Date: 09-04-2018
Abstract: To understand drug-protein dynamics, it is necessary to account for drug molecular flexibility and binding site plasticity. Herein, we exploit fluorescence from a tyrosine kinase inhibitor, AG1478, as a reporter of its conformation and binding site environment when complexed with its cognate kinase. Water-soluble kinases, aminoglycoside phosphotransferase APH(3')-Ia and mitogen-activated protein kinase 14 (MAPK14), were chosen for this study. On the basis of our prior work, the AG1478 conformation (planar or twisted) was inferred from the fluorescence excitation spectrum and the polarity of the AG1478-binding site was deduced from the fluorescence emission spectrum, while red-edge excitation shift (REES) probed the heterogeneity of the binding site (protein conformation and hydration) distributions in the protein conformational ensemble. In the AG1478-APH(3')-Ia complex, both twisted (or partially twisted) and planar AG1478 conformations were evidenced from emission wavelength-dependent excitation spectra. The binding site environment provided by APH(3')-Ia was moderately polar (λ
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D0RA10674G
Abstract: The global breakout of COVID-19 and raised death toll has prompted scientists to develop novel drugs capable of inhibiting SARS-CoV-2.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6NJ01909A
Abstract: A quantum mechanical rationale for the observed UV-Vis spectrum of anti-cancer drug AG-1478 was accomplished using two conformers.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.BMC.2016.08.069
Abstract: A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC
Publisher: Elsevier BV
Date: 12-2023
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7NJ03361C
Abstract: The ultimate understanding of drug–protein interactions relies on understanding drug behaviours in solution, at the molecular level.
Publisher: Informa UK Limited
Date: 30-04-2021
Publisher: Springer Science and Business Media LLC
Date: 24-11-2017
DOI: 10.1038/S41598-017-16583-Z
Abstract: Tyrosine kinase inhibitors (TKIs) are a major class of drug utilised in the clinic. During transit to their cognate kinases, TKIs will encounter different pH environments that could have a major influence on TKI structure. To address this, we report UV-Vis spectroscopic and computational studies of the TKI, AG1478, as a function of pH. The electronic absorption spectrum of AG1478 shifted by 10 nm (from 342 nm to 332 nm) from acid to neutral pH and split into two peaks (at 334 nm and 345 nm) in highly alkaline conditions. From these transitions, the pKa value was calculated as 5.58 ± 0.01. To compute structures and spectra, time-dependent density functional theory (TD-DFT) calculations were performed along with conductor-like polarizable continuum model (CPCM) to account for implicit solvent effect. On the basis of the theoretical spectra, we could assign the AG1478 experimental spectrum at acidic pH to a mixture of two twisted conformers (71% AG1478 protonated at quinazolyl nitrogen N(1) and 29% AG1478 protonated at quinazolyl nitrogen N(3)) and at neutral pH to the neutral planar conformer. The AG1478 absorption spectrum (pH 13.3) was fitted to a mixture of neutral (70%) and NH-deprotonated species (30%). These studies reveal a pH-induced conformational transition in a TKI.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2012
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.SAA.2016.04.009
Abstract: The effect of twenty-one solvents on the UV-Vis spectrum of the tyrosine kinase inhibitor AG-1478 was investigated. The absorption spectrum in the range 300-360nm consisted of two partially overlapping bands at approximately 340nm and 330nm. The higher energy absorption band was more sensitive to solvent and exhibited a peak position that varied from 327nm to 336nm, while the lower energy absorption band demonstrated a change in peak position from 340nm to 346nm in non-chlorinated solvents. The fluorescence spectrum of AG-1478 was particularly sensitive to solvent. The wavelength of peak intensity varied from 409nm to 495nm with the corresponding Stokes shift in the range of 64nm to 155nm (4536cm(-1) to 9210cm(-1)). We used a number of methods to assess the relationship between spectroscopic properties and solvent properties. The detailed analysis revealed that for aprotic solvents, the peak position of the emission spectrum in wavenumber scale correlated with the polarity (dielectric constant or ET(30)) of the solvent. In protic solvents, a better correlation was observed between the hydrogen bonding power of the solvent and the position of the emission spectrum. Moreover, the fluorescence quantum yields were larger in aprotic solvents as compared to protic solvents. This analysis underscores the importance of polarity and hydrogen-bonding environment on the spectroscopic properties of AG-1478. These studies will assume relevance in understanding the interaction of AG-1478 in vitro and in vivo.
Publisher: Future Science Ltd
Date: 10-2021
Abstract: Background: Although some benzimidazole-based anthelmintic drugs are found to possess anticancer activity, their modes of binding interactions have not been reported. Methodology: In this study, we aimed to investigate the binding interactions and electronic configurations of nine benzimidazole-based anthelmintics against one of the well-known cancer targets (tubulin protein). Results: Binding affinities of docked benzimidazole drugs into colchicine-binding site were calculated where flubendazole oxfendazole nocodazole mebendazole. Flubendazole was found to bind more efficiently with tubulin protein than other drugs. Quantum mechanics studies revealed that the electron density of HOMO of flubendazole and mebendazole together with their molecular electrostatic potential map are closely similar to that of nocodazole. Conclusion: Our study has ramifications for considering repurposing of flubendazole as a promising anticancer candidate.
Publisher: Medknow
Date: 2022
No related grants have been discovered for Muhammad Khattab.