Shape-based Machine Learning Models for the Potential Novel COVID-19 Protease Inhibitors Assisted by Molecular Dynamics Simulation

Background: The vast geographical expansion of novel coronavirus and an increasing number of COVID-19 affected cases have overwhelmed health and public health services. Artificial Intelligence (AI) and Machine Learning (ML) algorithms have extended their major role in tracking disease patterns, and in identifying possible treatments. Objective: This study aims to identify potential COVID-19 protease inhibitors through shape-based Machine Learning assisted by Molecular Docking and Molecular Dynamics simulations. Methods: 31 Repurposed compounds have been selected targeting the main coronavirus protease (6LU7) and a machine learning approach was employed to generate shape-based molecules starting from the 3D shape to the pharmacophoric features of their seed compound. Ligand-Receptor Docking was performed with Optimized Potential for Liquid Simulations (OPLS) algorithms to identify highaffinity compounds from the list of selected candidates for 6LU7, which were subjected to Molecular Dynamic Simulations followed by ADMET studies and other analyses. Results: Shape-based Machine learning reported remdesivir, valrubicin, aprepitant, and fulvestrant as the best therapeutic agents with the highest affinity for the target protein. Among the best shape-based compounds, a novel compound identified was not indexed in any chemical databases (PubChem, Zinc, or ChEMBL). Hence, the novel compound was named 'nCorv-EMBS'. Further, toxicity analysis showed nCorv-EMBS to be suitable for further consideration as the main protease inhibitor in COVID-19. Conclusion: Effective ACE-II, GAK, AAK1, and protease 3C blockers can serve as a novel therapeutic approach to block the binding and attachment of the main COVID-19 protease (PDB ID: 6LU7) to the host cell and thus inhibit the infection at AT2 receptors in the lung. The novel compound nCorv- EMBS herein proposed stands as a promising inhibitor to be evaluated further for COVID-19 treatment.