Abstract
The umbrella sampling (US) simulation is demonstrated to be an efficient approach for determining the unbinding pathway and binding affinity to the SARS-CoV-2 Mpro of small molecule inhibitors. The accuracy of US is in the same range as the linear interaction energy (LIE) and fast pulling of ligand (FPL) methods. In detail, the correlation coefficient between US and experiments does not differ from FPL and is slightly smaller than LIE. The root mean square error of US simulations is smaller than that of LIE. Moreover, US is better than FPL and poorer than LIE in classifying SARS-CoV-2 Mpro inhibitors owing to the reciever operating characteristic–area under the curve analysis. Furthermore, the US simulations also provide detailed insights on unbinding pathways of ligands from the binding cleft of SARS-CoV-2 Mpro. The residues Cys44, Thr45, Ser46, Leu141, Asn142, Gly143, Glu166, Leu167, Pro168, Ala191, Gln192 and Ala193 probably play an important role in the ligand dissociation. Therefore, substitutions at these points may change the mechanism of binding of inhibitors to SARS-CoV-2 Mpro.
Highlights
IntroductionHubei Province, China in December 2019 [1,2,3,4]
Twenty four three-dimensional structures of the solvated SARS-CoV-2 main protease (Mpro) + inhibitor were reported in the previous work [22], in which the structure of SARS-CoV-2 Mpro was downloaded from the protein data bank with identification of 6Y2F [66] and structure of ligands downloaded from the PubChem database [67]
The correlation between umbrella sampling (US) binding free energy and experiments is rather high with a value of R 1⁄4 0:66 + 0:13, which is in the same range of correlation with fast pulling of ligand (FPL) [22]
Summary
Hubei Province, China in December 2019 [1,2,3,4]. Since it has caused millions of deaths worldwide. Two vaccines for SARS-CoV-2 have recently been approved for emergency use by the US Food and Drug Administration [11], using the vaccines to create COVID-19 herd immunity may not be possible [12]. Especially, recent reports on new variants of SARS-CoV-2 appearing in the UK (B1.1.7) and South Africa (B1.351) can escape the neutralizing antibodies [13,14]
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