This project will perform classical molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations on two different drug targets of COVID-19, the SARS-CoV main protease and the NSP12 RNA-directed RNA polymerase. The crystal structure of the main protease as well as the complex of the protease with an a–ketoamide inhibitor have been very recently reported, this structure has been the focus of a concerted/world–wide drug discovery campaign. The crystal structure of the NSP12 RNA–directed RNA polymerase in complex with the NSP7 and NSP8 co–factors has also been recently reported, and shown to be highly similar to the SARS–CoV NSP12 polymerase. The proposed simulations will provide detailed insights on the chemical reaction mechanism of these two high value targets. The deep mechanistic understanding of covalent inhibitors for both of these high value targets will enable the refinement and further development of mechanism–based inhibitors by providing the ability to optimize transition state analogues as inhibitor leads.
This project is part of the COVID-19 HPC Consortium.
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