Eluxadoline for COVID-19

<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>

Abstract Using as a template the crystal structure of the SARS-CoV-2 main protease, we developed a pharmacophore model of functional centers of the protease inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of the SARS-CoV-2 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of the protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin—the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.