On the search for COVID-19 therapeutics: identification of potential SARS-CoV-2 main protease inhibitors by virtual screening, pharmacophore modeling and molecular dynamics

Abstract

COVID-19 also known as SARS-CoV-2 outbreak in late 2019 and its worldwide pandemic spread has taken the world by surprise. The minute-to-minute increasing coronavirus cases (>85 M) and progressive deaths (≈1.8 M) calls for finding a cure to this devastating pandemic. While there have been many attempts to find biologically active molecules targeting SARS-CoV-2 for treatment of this viral infection, none has found a way to the clinic yet. In this study, a 3-feature structure-based pharmacophore model was designed for SARS-CoV-2 main protease (MPro) that plays a vital role in the viral cellular penetration. High throughput virtual screening of the lead-like ZINC library was then performed to find a potent inhibitor employing the predesigned pharmacophore. In-silico pharmacokinetics/toxicity prediction study was subsequently applied towards the best hits. Finally, a 50 ns molecular dynamics simulation was carried out for the best hit and compared to the co-crystallized ligand where the hit compound displayed high binding and comparable interactions. The results identified new hits for SARS-CoV-2 MPro inhibition showing good docking score, pharmacokinetics and toxicity profile, drug-likeness, high binding energy in addition to a promising synthetic accessibility. Identifying new small compounds as potential leads for inhibiting SARS-CoV-2 is a very important step towards designing a synthesizing of promising drug candidates. Communicated by Ramaswamy H. Sarma