Drug molecules targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could save millions of lives from COVID-19 pandemic, and the USFDA has authorized emergency use of Paxlovid, an investigational medicine, for the treatment of mild-to-moderate COVID-19 in adults and children. However, there is limited information about the safety and effectiveness of using Paxlovid to treat people with mild-to-moderate COVID-19. There is a medical need to develop potential and safe inhibitors of coronavirus replication in preparation for future outbreaks. The Main protease (Mpro) enzyme plays a crucial role in SARS-CoV-2 replication,it is a highly conserved enzyme and lacks closely related homologues in humans, rendering it one of the most attractive therapeutic targets for small molecule inhibitors. The catalytic reaction in SARS-Cov-2 Mpro is activated by a proton transfer at the active site from Cys145 to His41. Using medicinal chemistry and rational drug design strategies, we explored a highly focused library of compounds containing covalent novel aza-peptide warheads designed to target the active site Cys145 of SARS-CoV-2 Mpro. The initial screening was guided by precision docking of 192 potential inhibitors using Schrödinger (Glide) which led to the identification of eight hit compounds. Further, molecular dynamic (MD) simulations and covalent docking of the four best compounds produced stable complexes with the ligands. The ADMET property prediction and free energy calculations were carried out for these virtual leads, which have the potential for the better inhibition of SARS-CoV-2 Main protease.

<i>In-silico</i> guided design, screening, and molecular dynamic simulation studies for the identification of potential SARS-CoV-2 main protease inhibitors for long term COVID-19 treatment

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In-silico guided design, screening, and molecular dynamic simulation studies for the identification of potential SARS-CoV-2 main protease inhibitors for long term COVID-19 treatment