ORCID Profile
0000-0001-5508-6153
Current Organisation
Fiona Stanley Hospital
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Publisher: Elsevier BV
Date: 12-2009
Publisher: MDPI AG
Date: 13-09-2011
Publisher: Springer Science and Business Media LLC
Date: 28-01-2012
Publisher: MDPI AG
Date: 05-06-2021
DOI: 10.3390/PR9061004
Abstract: Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00751H
Abstract: Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI.
Publisher: American Chemical Society (ACS)
Date: 25-07-2017
Publisher: MDPI AG
Date: 22-05-2014
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1007/S12272-012-0104-0
Abstract: Two series, a and b, of 3-cyclopentyl or (3-cyclohexyl)-5-substituted-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thiones (THTT) 2a-9a and 3b, 4b, 6b-9b, were synthesized to develop new cell cycle inhibitors. Variable and promising in vitro antiproliferative activities were shown with the synthesized THTT derivatives. Compound 5a with a 5-cyclopentyl group on position-3 and a glutamine residue on position-5 of the THTT moiety showed maximum activity (IC(50) = 8.98 μM). Compound 5a possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. There is no evident relationship between the cytotoxic activity of the tested compounds and their lipophilicity. In addition, a pharmacophore based study was performed to explain the biological activity on structural bases. A successful model was generated with a good correlation with the observed activity.
Publisher: Beilstein Institut
Date: 15-04-2015
DOI: 10.3762/BJOC.11.54
Abstract: Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new ex les of the hydroxy-8a,13-dihydroazepino[1,2- a :3,4- b ']diindol-14(8 H )-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6 H -6,8a-epoxyazepino[1,2- a :3,4- b ']diindol-14(13 H )-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2- a ]indol)-3-one (65%) and pyrido[1,2,3- s , t ]indolo[1,2- a ]azepino[3,4- b ]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N , O -diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1 R ,8a S ,17a S )-rel-1,2-dihydro-1-vinyl-8 H ,17H,9 H -benz[2',3']pyrrolizino[1',7 a ':2,3]pyrido[1,2- a ]indole-8,17-(2 H ,9 H )-dione heterocyclic system.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6OB00606J
Abstract: A series of quinolone-2-(1 H )-ones derived from a Ugi-Knoevenagel three- and four-component reaction were prepared exhibiting low micromolar cytotoxicity against a panel of eight human cancer cell lines known to possess the Hedgehog Signalling Pathway (HSP) components, as well as the seminoma TCAM-2 cell line.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2014
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.EJMECH.2014.06.070
Abstract: Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.
Publisher: Elsevier BV
Date: 11-2007
DOI: 10.1016/J.BMC.2007.07.044
Abstract: A new series of 1,3,4-thiadiazole-2-thione derivatives have been prepared and assayed for the inhibition of three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX. Against hCA I the investigated thiones, showed inhibition constants in the range of 2.55-222 microM, against hCA II in the range of 2.0-433 microM, and against hCA IX in the range of 1.25-148 microM. Compound 5c, 4-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)-1-(5-nitro-2-oxoindolin-3-ylidene)semicarbazide showed interesting inhibition of the tumor-associated hCA IX with K(I) value of 1.25 microM, being the first non-sulfonamide type inhibitor of such activity. This result is rather important taking into consideration the known antitumor activity of thiones. In addition, docking of the tested compounds into CA II active site was performed in order to predict the affinity and orientation of these compounds at the isozyme active site. The results showed similar orientation of the target compounds at CA II active site compared with reported sulfonamide type CAIs with the thione group acting as a zinc-binding moiety.
Publisher: Informa UK Limited
Date: 20-10-2009
DOI: 10.1080/14756360802361514
Abstract: A linear quantitative structure-activity relationship (QSAR) study that encodes various aspects of physicochemical, topological and electronic descriptors has been developed for a series of 1,3,4-thiadiazole-2-thione derivatives (1a-r and 2a-c). The carbonic anhydrase IX inhibitory activity of the candidates under study (1a-r and 2a-c) were correlated to the selected parameters using stepwise linear regression analyses to achieve the best QSAR model. Promising results were obtained with the employed tetra-parametric model indicating that the information approach used in the present investigation is quite useful for modeling carbonic anhydrase IX inhibitors.
Publisher: Elsevier
Date: 2013
No related grants have been discovered for Mohammed Kamal Abdel-Hamid Amin.