The COVID-19 pandemic presents an unprecedented challenge for the pharmaceutical industry and academic scientists, alike. While in most circumstances, novel therapeutics can be developed using a wide range of strategies, the immediate need for effective, safe, and globally-scalable antivirals severely restricts the plausibility of many options. Thus, the research community has turned toward numerous techniques that shorten the bench-to-bedside pipeline, including in silico candidate screening and drug repurposing using FDA-approved chemical libraries. Previously reported studies indicate mixed success; however, our reviewers found promise in a recently unverified study published by Ghahremanpour and colleagues. If verified, their findings offer (1) a useful strategy for in silico screening of FDA-approved candidate therapeutics, (2) a list of FDA-approved compounds that effectively inhibit Mpro activity, and (3) defining drug-protein binding characteristics useful for lead optimization.
Their study, posted on August 20th, sought to identify FDA-approved small molecules that inhibit Mpro, the main protease of SARS-CoV-2. The authors put forth a consensus molecular docking protocol that effectively identified 42 candidates from a 2000-compound library. Secondary in silico screening further identified the 17 most promising hits, 14 of which exhibited activity against Mpro through wet bench validation. Finally, molecular docking of validated hits revealed a common “cloverleaf” binding pattern that defined the drug-protein interaction.
Rapid Reviews: COVID-19 sought out expert peer reviewers to assess the validity of the authors’ claims. One reviewer felt the manuscript would be more informative if the report included a more rigorous justification for the experimental approach, yet deemed the conclusions drawn from the study Reliable. The second reviewer indicated the study was well-executed and deemed the findings Strong. Additional reviews will be published as they are received. While follow-up studies and further revision should be pursued, the conclusions presented in this pre-print are appropriately drawn, compelling, and potentially useful for those developing therapeutics to combat the COVID-19 pandemic.