Design and Validation of FRESH, a Drug Discovery Paradigm Resting on Robust Chemical Synthesis

A method capable of identifying novel synthetic targets for small molecule lead optimization has been developed. The FRESH (<i>FR</i>agment-based <i>E</i>xploitation of modular <i>S</i>ynthesis by v<i>H</i>TS) approach relies on a multistep synthetic route to a target series of compounds devised by a close collaboration between synthetic and computational chemists. It combines compound library generation, quantitative structure–acitvity relationship construction, fragment processing, virtual high throughput screening and display of results within the Pipeline Pilot framework. Outcomes enumerate tailored selection of novel synthetic targets with improved potency and optimized physical properties for an emerging compound series. To validate the application of FRESH, three retrospective case studies have been performed to pinpoint reported potent analogues. One prospective case study was performed to demonstrate that FRESH is able to capture additional potent analogues

Design and Optimization of Novel Competitive, Non-peptidic, SARS-CoV‑2 M^pro 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