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

TLDR

The SARS‑CoV‑2 3CLpro shares 96% sequence identity with the SARS‑CoV enzyme, with conserved catalytic, substrate‑binding, and dimerization residues, suggesting that inhibitors developed for SARS‑CoV may be applicable to SARS‑CoV‑2. Using the SARS‑CoV crystal structure, the authors built a 3D model of SARS‑CoV‑2 3CLpro and performed virtual screening of commercially available drugs, identifying 16 repurposing candidates. Among the candidates, ledipasvir and velpatasvir, as well as the combination drugs Epclusa and Harvoni, were highlighted for their potential antiviral activity against SARS‑CoV‑2 with minimal side effects.

Abstract

<ns4:p>We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL<ns4:sup>pro</ns4:sup>) 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<ns4:sup>pro</ns4:sup> 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.</ns4:p>