Toward the Discovery of SARS-CoV-2 Main Protease Inhibitors: Exploring Therapeutic Potentials of Evodiamine and Its Derivatives, Virtual Screening, Molecular Docking, and Molecular Dynamic Studies

Continuous scientific research is necessary to help in the discovery of new promising remedies for the treatment of COVID-19, caused by the SARS-CoV-2 virus. This current research was aimed at identifying potential novel inhibitors of the SARS-CoV-2 main protease, which represents one of the most important targets in the viral life cycle. Protein data bank file ID: 7JQ2 was used containing the co-crystallized inhibitor MPI5 with the Main protease. A virtual screening process for natural evodiamine compounds was performed through absorption, distribution, metabolism, elimination, and toxicity studies, and the promising hits were docked into the binding site of the enzyme. 13-(4-Chlorobenzoyl)-10-hydroxy-14-methyl-8,13,13 b,14-tetrahydroindolo[2′,3′:3,4]pyrido[2,1- b]-quinazolin-5(7 H)-one (29) interacted favorably with the enzyme; it showed high similarity to MPI5. Molecular dynamic simulations for 29 proved the stability of its binding to SARS-CoV-2 protease over 100 ns; subsequent MMGBSA analysis also supported this principle. Furthermore, 29 elucidated higher limiting action on enzymatic behavior throughout the whole process when compared to MPI5. This provides sufficient evidence for the potential of evodiamine compounds in modern antiviral research, especially compound 29, against the modern COVID-19 pandemic.