Zaleplon for COVID-19

AbstractHere, we introduce the use of ANI-ML potentials as a rescoring function in the host–guest interaction in molecular docking. Our results show that the “docking power” of ANI potentials can compete with the current scoring functions at the same level of computational cost. Benchmarking studies on CASF-2016 dataset showed that ANI is ranked in the top 5 scoring functions among the other 34 tested. In particular, the ANI predicted interaction energies when used in conjunction with GOLD-PLP scoring function can boost the top ranked solution to be the closest to the x-ray structure. Rapid and accurate calculation of interaction energies between ligand and protein also enables screening of millions of drug candidates/docking poses. Using a unique protocol in which docking by GOLD-PLP, rescoring by ANI-ML potentials and extensive MD simulations along with end state free energy methods are combined, we have screened FDA approved drugs against the SARS-CoV-2 main protease (Mpro). The top six drug molecules suggested by the consensus of these free energy methods have already been in clinical trials or proposed as potential drug molecules in previous theoretical and experimental studies, approving the validity and the power of accuracy in our screening method.

AbstractThe emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.