Molecular Docking, ADMET Analysis and Molecular Dynamics (MD) Simulation to Identify Synthetic Isoquinolines as Potential Inhibitors of SARS-CoV-2 M^PRO

Background: The rapidly widespread SARS-CoV-2 infection has affected millions worldwide, thus becoming a global health emergency. Although vaccines are already available, there are still new COVID-19 cases daily worldwide, mainly due to low immunization coverage and the advent of new strains. Therefore, there is an utmost need for the discovery of lead compounds to treat COVID-19. Objective: Considering the relevance of the SARS-CoV-2 M^PRO in viral replication and the role of the isoquinoline moiety as a core part of several biologically relevant compounds, this study aimed to identify isoquinoline-based molecules as new drug-like compounds, aiming to develop an effective coronavirus inhibitor. Methods: 274 isoquinoline derivatives were submitted to molecular docking interactions with SARS-CoV-2 M^PRO (PDB ID: 7L0D) and drug-likeness analysis. The five best-docked isoquinoline derivatives that did not violate any of Lipinskie's or Veber's parameters were submitted to ADMET analysis and molecular dynamics (MD) simulations. Results: The selected compounds exhibited docking scores similar to or better than chloroquine and other isoquinolines previously reported. The fact that the compounds interact with residues that are pivotal for the enzyme's catalytic activity, and show the potential to be orally administered makes them promising drugs for treating COVID-19. Conclusion: Ultimately, MD simulation was performed to verify ligand-protein complex stability during the simulation period.