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

F1000Res. 2020 Feb 21;9:129. doi: 10.12688/f1000research.22457.2. eCollection 2020.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzimidazoles / pharmacology*
  • Betacoronavirus / drug effects*
  • COVID-19
  • Carbamates / pharmacology*
  • Coronavirus 3C Proteases
  • Coronavirus Infections* / drug therapy
  • Cysteine Endopeptidases / chemistry*
  • Drug Repositioning
  • Fluorenes / pharmacology*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Pandemics*
  • Pneumonia, Viral* / drug therapy
  • SARS-CoV-2
  • Viral Nonstructural Proteins / chemistry*


  • Benzimidazoles
  • Carbamates
  • Fluorenes
  • Heterocyclic Compounds, 4 or More Rings
  • Viral Nonstructural Proteins
  • ledipasvir
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases
  • velpatasvir

Supplementary concepts

  • COVID-19
  • severe acute respiratory syndrome coronavirus 2

Grants and funding

We acknowledge support from the Innovation and Technology Commission of Hong Kong, the Hong Kong Polytechnic University and the Life Science Area of Strategic Fund 1-ZVH9.