Assessing potential inhibitors of SARS-CoV-2 main protease from available drugs using free energy perturbation simulations
Sơn Tùng Ngô, Hung Minh Nguyen, Le Thi Thuy Huong, Phạm Minh Quân, Vi Khanh Truong, Nguyễn Thanh Tùng, Van V. Vu
Abstract
= 0.82 ± 0.08). This result clearly shows that FEP is the most accurate method available to predict the binding affinity of SARS-CoV-2 Mpro + ligand complexes. We subsequently used FEP to validate the top 33 compounds screened with molecular docking from the ZINC15 database. Thirteen of these compounds were predicted to bind strongly to SARS-CoV-2 Mpro, most of which are currently used as drugs for various diseases in humans. Notably, delamanid, an anti-tuberculosis drug, was predicted to inhibit SARS-CoV-2 Mpro in the nanomolar range. Because both COVID-19 and tuberculosis are lung diseases, delamanid has higher probability to be suitable for treating COVID-19 than other predicted compounds. Analysis of the complexes of SARS-CoV-2 Mpro and the top inhibitors revealed the key residues involved in the binding, including the catalytic dyad His14 and Cys145, which is consistent with the structural studies reported recently.