Phytochemicals from Leucas zeylanica Targeting Main Protease of SARS-CoV-2: Chemical Profiles, Molecular Docking, and Molecular Dynamics Simulations

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a contemporary coronavirus, has impacted global economic activity and has a high transmission rate. As a result of the virus's severe medical effects, developing effective vaccinations is vital. Plant-derived metabolites have been discovered as potential SARS-CoV-2 inhibitors. The SARS-CoV-2 main protease (M^pro) is a target for therapeutic research because of its highly conserved protein sequence. Gas chromatography-mass spectrometry (GC-MS) and molecular docking were used to screen 34 compounds identified from <i>Leucas zeylanica</i> for potential inhibitory activity against the SARS-CoV-2 M^pro. In addition, prime molecular mechanics-generalized Born surface area (MM-GBSA) was used to screen the compound dataset using a molecular dynamics simulation. From molecular docking analysis, 26 compounds were capable of interaction with the SARS-CoV-2 M^pro, while three compounds, namely 11-oxa-dispiro[4.0.4.1]undecan-1-ol (-5.755 kcal/mol), azetidin-2-one 3,3-dimethyl-4-(1-aminoethyl) (-5.39 kcal/mol), and lorazepam, 2TMS derivative (-5.246 kcal/mol), exhibited the highest docking scores. These three ligands were assessed by MM-GBSA, which revealed that they bind with the necessary M^pro amino acids in the catalytic groove to cause protein inhibition, including Ser144, Cys145, and His41. The molecular dynamics simulation confirmed the complex rigidity and stability of the docked ligand-M^pro complexes based on the analysis of mean radical variations, root-mean-square fluctuations, solvent-accessible surface area, radius of gyration, and hydrogen bond formation. The study of the postmolecular dynamics confirmation also confirmed that lorazepam, 11-oxa-dispiro[4.0.4.1]undecan-1-ol, and azetidin-2-one-3, 3-dimethyl-4-(1-aminoethyl) interact with similar M^pro binding pockets. The results of our computerized drug design approach may assist in the fight against SARS-CoV-2.