Abstract
The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires treatments with rapid clinical translatability. Here we develop a multi-target and multi-ligand virtual screening method to identify FDA-approved drugs with potential activity against SARS-CoV-2 at traditional and understudied viral targets. 1,268 FDA-approved small molecule drugs were docked to 47 putative binding sites across 23 SARS-CoV-2 proteins. We compared drugs between binding sites and filtered out compounds that had no reported activity in an in vitro screen against SARS-CoV-2 infection of human liver (Huh-7) cells. This identified 17 “high-confidence”, and 97 “medium-confidence” drug-site pairs. The “high-confidence” group was subjected to molecular dynamics simulations to yield six compounds with stable binding poses at their optimal target proteins. Three drugs-amprenavir, levomefolic acid, and calcipotriol-were predicted to bind to 3 different sites on the spike protein, domperidone to the Mac1 domain of the non-structural protein (Nsp) 3, avanafil to Nsp15, and nintedanib to the nucleocapsid protein involved in packaging the viral RNA. Our “two-way” virtual docking screen also provides a framework to prioritize drugs for testing in future emergencies requiring rapidly available clinical drugs and/or treating diseases where a moderate number of targets are known.
【초록키워드】 Treatment, SARS-CoV-2, coronavirus, pandemic, SARS-COV-2 infection, Virtual screening, drug, docking, molecular dynamics, in vitro, severe acute respiratory syndrome Coronavirus, FDA-approved drugs, molecular dynamics simulations, Spike protein, binding site, nucleocapsid protein, Molecular dynamics simulation, Domperidone, cells, non-structural protein, target, small molecule, Viral RNA, targets, disease, moderate, binding, Nsp15, NSP, SARS-CoV-2 proteins, framework, Amprenavir, Nintedanib, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, FDA-approved drug, Compound, domain, target proteins, human liver, Huh-7, Mac1, small molecule drugs, avanafil, calcipotriol, levomefolic acid, predicted, identify, develop, caused, involved, reported, provide, the spike protein, had no, docked, filtered, small molecule drug, 【제목키워드】 drug, target, Analysis, SARS-CoV-2 protein, clinically,