Design and Optimization of Novel Competitive, Non-peptidic, SARS-CoV-2 M<sup>pro</sup> Inhibitors
Leon Jacobs, Aletta van der Westhuyzen, Nicole Pribut, Zackery W. Dentmon, Dan Cui, Michael P. D’Erasmo, Perry W. Bartsch, Ken Liu, Robert M. Cox, Sujay F. Greenlund, Richard K. Plemper, Deborah G. Mitchell, Joshua B. Marlow, Meghan K. Andrews, Rebecca E. Krueger, Zachary M. Sticher, Alexander A. Kolykhalov, Michael G. Natchus, Bin Zhou, Stephen C. Pelly, Dennis C. Liotta
Abstract
High Resolution Image Download MS PowerPoint Slide The SARS-CoV-2 main protease (M pro ) has been proven to be a highly effective target for therapeutic intervention, yet only one drug currently holds FDA approval status for this target. We were inspired by a series of publications emanating from the Jorgensen and Anderson groups describing the design of potent, non-peptidic, competitive SARS-CoV-2 M pro inhibitors, and we saw an opportunity to make several design modifications to improve the overall pharmacokinetic profile of these compounds without losing potency. To this end, we created a focused virtual library using reaction-based enumeration tools in the Schrödinger suite. These compounds were docked into the M pro active site and subsequently prioritized for synthesis based upon relative binding affinity values calculated by FEP+. Fourteen compounds were selected, synthesized, and evaluated both biochemically and in cell culture. Several of the synthesized compounds proved to be potent, competitive M pro inhibitors with improved metabolic stability profiles.