Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro) structure: virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates

Yu Wai Chen, Chin-Pang Bennu Yiu, Kwok-Yin Wong, Yu Wai Chen, Chin-Pang Bennu Yiu, Kwok-Yin Wong

Abstract

We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache. The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.

Keywords: 2019-nCoV; 3C-like protease; COVID-19; HCV; Hepatitis C virus; SARS; antiviral; coronavirus; drug repurpose; ledipasvir; molecular modelling; velpatasvir; virtual screening.

Conflict of interest statement

No competing interests were disclosed.

Copyright: © 2020 Chen YW et al.

Figures

Figure 1.. Virtual screening results for the…
Figure 1.. Virtual screening results for the SARS-CoV-2 3CL pro protease.
Docking of representative drugs into the active sites of A chain (A,B,C) and that of B chain (D,E,F). The catalytic residue surfaces are coloured in yellow. Atom colours of drug: C: cyan; O: red; N: blue; H: white; S: yellow; only polar hydrogens are shown. Prepared with PyMOL.

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