1 research outputs found
Design and Optimization of Novel Competitive, Non-peptidic, SARS-CoV‑2 M<sup>pro</sup> Inhibitors
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