Allosteric site of SARS-CoV-2 main protease as drug target in the presence of its emerging mutations

Olivier Sheik Amamuddy1, Gennady M. Verkhivker 2,3,4 and Özlem Tastan Bishop1

1 Research Unit in Bioinformatics, Department of Microbiology and Biochemistry, Rhodes University, Grahamstown 6140, South Africa

2 Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA

3 Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA

4 Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

This presentation will highlight some of the important findings from our recent article [1]. In this study, we aimed to identify the effect of early pandemic stage mutations in the SARS-CoV-2 drug target main protease, which is also known as Mpro. Understanding the effect of mutations at molecular level is highly important for drug design purposes as it would give insights toward the behavior of the protein and also the active site. We also investigated the presence of potential allosteric site(s) as an alternative drug targeting site. We combined computational approaches including database preparation, variant retrieval, homology modeling, dynamic residue network (DRN) analysis, and relevant conformation retrieval from 1-D kernel density estimates from reaction coordinates. We detected novel results including mirrored allosteric sites, widening and modification of the substrate binding sites and high N-finger instability. Although there are several drug discovery studies on SARS-CoV-2 Mpro, to our knowledge this is first publication in the field investigating the mutational effects and proposing a novel drug targeting site. Further, our approach has a number of novel aspects and is applicable to other coronaviral proteins.

[1] Sheik Amamuddy O, Verkhivker GM, Tastan Bishop Ö. Impact of early pandemic stage mutations on molecular dynamics of SARS-CoV-2 Mpro [published online ahead of print, 2020 Aug 27]. J Chem Inf Model. 2020;10.1021/acs.jcim.0c00634. doi:10.1021/acs.jcim.0c00634