COVID-19 is a devastating respiratory and inflammatory illness caused by a new coronavirus that is rapidly spreading throughout the human population. Over the past 12 months, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has already infected over 160 million (>20% located in United States) and killed more than 3.3 million people around the world (>20% deaths in USA). As we face one of the most challenging times in our recent history, there is an urgent need to identify drug candidates that can attack SARS-CoV-2 on multiple fronts. We have therefore initiated a computational dynamics drug pipeline using molecular modeling, structure simulation, docking and machine learning models to predict the inhibitory activity of several million compounds against two essential SARS-CoV-2 viral proteins and their host protein interactors—S/Ace2, Tmprss2, Cathepsins L and K, and Mpro—to prevent binding, membrane fusion and replication of the virus, respectively. All together, we generated an ensemble of structural conformations that increase high-quality docking outcomes to screen over >6 million compounds including all FDA-approved drugs, drugs under clinical trial (>3000) and an additional >30 million selected chemotypes from fragment libraries. Our results yielded an initial set of 350 high-value compounds from both new and FDA-approved compounds that can now be tested experimentally in appropriate biological model systems. We anticipate that our results will initiate screening campaigns and accelerate the discovery of COVID-19 treatments.
【저자키워드】 Drug discovery, COVID, multi-drug therapy, bioprinting, TMPRSS2, 【초록키워드】 COVID-19, SARS-CoV-2, coronavirus, clinical trial, Viral proteins, drug, docking, outcome, severe acute respiratory syndrome Coronavirus, FDA-approved drugs, virus, COVID-19 treatments, Replication, MPro, Protein, death, membrane fusion, United States, molecular, respiratory, USA, predict, binding, cathepsin, New coronavirus, Inflammatory, human population, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, drug candidates, Compound, conformation, host protein, inhibitory activity, drug candidate, model systems, over, Prevent, initial, SARS-CoV-2 viral, selected, responsible, tested, identify, caused, initiated, accelerate, chemotype, machine learning model, 【제목키워드】 COVID-19, Engagement, target, Synergetic,