posted on 2023-09-28, 10:43authored byLeon 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 Mitchell, Joshua Marlow, Meghan K. Andrews, Rebecca E. Krueger, Zachary M. Sticher, Alexander A. Kolykhalov, Michael G. Natchus, Bin Zhou, Stephen C. Pelly, Dennis C. Liotta
The SARS-CoV-2 main protease (Mpro) 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 Mpro 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 Mpro 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 Mpro inhibitors
with improved metabolic stability profiles.