Evaluating phytochemicals as SARS-CoV-2 papain-like protease inhibitors: a docking, ADMET and molecular dynamics investigation

The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants necessitates the urgent search for antiviral therapies despite the availability of vaccines and approved antiviral drugs indicated for the treatment of COVID-19. Targeting SARS-CoV-2 papain-like protease (SC2-PL^pro) is a therapeutic strategy for new drug development due to its dual role in viral replication and host innate immunity suppression. Thus, this study aimed to explore potential phytochemical inhibitors against SC2-PL^pro from a constructed phytochemical library along with two positive controls using virtual screening methods. Molecular docking was employed to calculate binding affinity of each compound within the S3/S4 binding pocket of SC2-PL^pro. Based on the docking results, three phytochemicals were subjected to molecular docking with SARS-CoV-2 variants and non-covalent interaction analysis utilizing the Discovery Studio Visualizer software. Further, their pharmacokinetics and toxicity descriptors were evaluated using molinspiration, pkCSM and StopTox web servers. The best docked protein–ligand complexes were subjected to molecular dynamics (MD) simulation for 100 ns. Among all tested phytochemicals, hirsutenone, broussoflavan A and broussochalcone A demonstrated the strongest binding affinity (− 8.23, − 8.13, and − 7.78 kcal/mol) and the lowest inhibition constant (920.39 nM, 1.1 µM, and 1.97 µM) toward the binding pocket of SC2-PL^pro. In silico pharmacokinetics and toxicity predictions showed these three compounds to be water-soluble, non-mutagenic, non-hepatotoxic, and biologically safe. MD simulations confirmed the stability of the broussoflavan A and broussochalcone A complexes, while hirsutenone displayed lower stability. Therefore, broussoflavan A and broussochalcone A show promise as lead compounds for further drug discovery efforts against COVID-19.

Graphical Abstract