Biological and Medicinal Chemistry

Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like Protease (3CLpro) Structure: Virtual Screening Reveals Velpatasvir, Ledipasvir, and Other Drug Repurposing Candidates



We prepared the three-dimensional model of the 2019-nCoV 3C-like protease (3CLpro) 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 in the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its 2019-nCoV counterpart. With the 3CLpro 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 2019-nCoV 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.


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Supplementary material

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Prediction nCoV-2019 3CL v2.9T Supp