Inhibitory potential of repurposed drugs against the SARS-CoV-2 main protease: a computational-aided approach

被引:25
作者
Fadaka, Adewale Oluwaseun [1 ]
Aruleba, Raphael Taiwo [2 ]
Sibuyi, Nicole Remaliah Samantha [1 ]
Klein, Ashwil [3 ]
Madiehe, Abram Madimabe [1 ,4 ]
Meyer, Mervin [1 ]
机构
[1] Univ Western Cape, Dept Biotechnol, Dept Sci & Innovat, Fac Nat Sci,Mintek Nanotechnol Innovat Ctr, Bellville, South Africa
[2] Univ Cape Town, Dept Mol & Cell Biol, Cape Town, South Africa
[3] Univ Western Cape, Dept Biotechnol, Fac Nat Sci, Bellville, South Africa
[4] Univ Western Cape, Dept Biotechnol, Nanobiotechnol Res Grp, Fac Nat Sci, Bellville, South Africa
关键词
Protease inhibitor; SARS-CoV-2; COVID-19; lamivudine; lopinavir; docking; Mpro; MOLECULAR DOCKING; PRADIMICIN-A; ACCURATE PREDICTION; LOPINAVIR/RITONAVIR; TRANSMISSION; DYNAMICS; SARS;
D O I
10.1080/07391102.2020.1847197
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The exponential increase in cases and mortality of coronavirus disease (COVID-19) has called for a need to develop drugs to treat this infection. Using in silico and molecular docking approaches, this study investigated the inhibitory effects of Pradimicin A, Lamivudine, Plerixafor and Lopinavir against SARS-CoV-2 M-pro. ADME/Tox of the ligands, pharmacophore hypothesis of the co-crystalized ligand and the receptor, and docking studies were carried out on different modules of Schrodinger (2019-4) Maestro v12.2. Among the ligands subjected to ADME/Tox by QikProp, Lamivudine demonstrated drug-like physico-chemical properties. A total of five pharmacophore binding sites (A3, A4, R9, R10, and R11) were predicted from the co-crystalized ligand and the binding cavity of the SARS-CoV-2 M-pro. The docking result showed that Lopinavir and Lamivudine bind with a higher affinity and lower free energy than the standard ligand having a glide score of -9.2 kcal/mol and -5.3 kcal/mol, respectively. Plerixafor and Pradimicin A have a glide score of -3.7 kcal/mol and -2.4 kcal/mol, respectively, which is lower than the co-crystallized ligand with a glide score of -5.3 kcal/mol. Molecular dynamics confirmed that the ligands maintained their interaction with the protein with lower RMSD fluctuations over the trajectory period of 100 nsecs and that GLU166 residue is pivotal for binding. On the whole, present study specifies the repurposing aptitude of these molecules as inhibitors of SARS-CoV-2 M-pro with higher binding scores and forms energetically stable complexes with M-pro. Communicated by Ramaswamy H. Sarma
引用
收藏
页码:3416 / 3427
页数:12
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