A dynamic structural model of the SARS-CoV-2 main protease to guide drug design and repurposing

In the race to discover an effective treatment for COVID-19, the SARS-CoV-2 main protease is an attractive target protein. Molecular docking and in vitro screening studies have quickly produced drug candidates that include FDA-approved drugs and novel compounds. With so many candidates and limited time, we aim to provide a molecular structural prediction for why some potential inhibitors might be more effective than others. Molecular dynamics (MD) simulations were critical in the rational design of HIV protease inhibitors and were able to predict the impact of mutations driving drug resistance. We intend to carve a similar path here—we propose to carry out microsecond MD simulations of the SARS-CoV-2 protease bound to inhibitors, some FDA-approved for the treatment of HIV or HCV, and some novel compounds that have emerged from recent SARS protease docking and structure-based design. The goals are to (1) establish molecular principles for predicting the best SARS protease inhibitors, (2) create a dynamic structural model that informs how inhibitors could be modified for higher efficacy, and (3) create a dynamic structural model that predicts the impact of SARS-CoV-2 mutations on drug resistance.