Profiling Molecular Simulations of SARS-CoV-2 Main Protease (Mpro) Binding to Repurposed Drugs Using Neural Network Force Fields

With the current pandemic situation caused by a novel coronavirus disease (COVID-19), there is an urgent call to develop a working therapeutic against it. Efficient computations aid to minimize the efforts by identifying a subset of drugs that can potentially bind to COVID-19 main protease or target protein (M^PRO). The results of computations are always accompanied by their accuracy which depends on the details described by the model used. Machine learning models trained on millions of points and with unmatched accuracies are the best bet to employ in the process. In this work, I first identified and described the interaction sites of M^PRO protein using a geometric deep learning model. Secondly, I conducted virtual screening (at one of the sites identified) on FDA approved drugs and picked 91 drugs having the highest binding affinity (below -8.0 kcal/mol). Then, I carried out 10 ns of molecular dynamics (MD) simulations using classical force fields and classified 37 drugs to be binding (includes drugs like Lopinavir, Saquinavir, Indinavir etc.) based on RMSD between MD-binding trajectories. To drastically improve the dynamics profile of selected 37 drugs, I brought in the highly accurate neural network force field (ANI) trained on coupled-cluster methods (CCSD(T)/CBS) data points and performed 1 ns of binding dynamics of each drug with protein. With the accurate approach, 19 drugs were qualified based on their RMSD cutoffs, and again with their free energy (ANI/MM/PBSA) computations another 7 drugs were rejected. The final selection of 12 drugs was validated based on MD trajectory clustering approach where 11 of 12 drugs (Targretin, Eltrombopag, Rifaximin, Deflazacort, Ergotamine, Doxazosin, Lastacaft, Rifampicin, Victrelis, Trajenta, Toposar, and Indinavir) were confirmed to be binding. Further investigations were made to study their interactions with the protein and an accurate 2D- interaction map was generated. These findings and mapping of drug-protein interactions are highly accurate and could be potentially used to guide rational drug discovery against the COVID-19.