Structure-Based Virtual Screening, Docking, ADMET, Molecular Dynamics, and MM-PBSA Calculations for the Discovery of Potential Natural SARS-CoV-2 Helicase Inhibitors from the Traditional Chinese Medicine

Abstract

Continuing our antecedent work against COVID-19, a set of 5956 compounds of traditional Chinese medicine have been virtually screened for their potential against SARS-CoV-2 helicase (PDB ID: 5RMM). Initially, a fingerprint study with VXG, the ligand of the target enzyme, disclosed the similarity of 187 compounds. Then, a molecular similarity study declared the most similar 40 compounds. Subsequently, molecular docking studies were carried out to examine the binding modes and energies. Then, the most appropriate 26 compounds were subjected to in silico ADMET and toxicity studies to select the most convenient inhibitors to be: (1R,2S)-ephedrine (57), (1R,2S)-norephedrine (59), 2-(4-(pyrrolidin-1-yl)phenyl)acetic acid (84), 1-phenylpropane-1,2-dione (195), 2-methoxycinnamic acid (246), 2-methoxybenzoic acid (364), (R)-2-((R)-5-oxopyrrolidin-3-yl)-2-phenylacetic acid (405), (Z)-6-(3-hydroxy-4-methoxystyryl)-4-methoxy-2H-pyran-2-one (533), 8-chloro-2-(2-phenylethyl)-5,6,7-trihydroxy-5,6,7,8-tetrahydrochromone (637), 3-((1R,2S)-2-(dimethylamino)-1-hydroxypropyl)phenol (818), (R)-2-ethyl-4-(1-hydroxy-2-(methylamino)ethyl)phenol (5159), and (R)-2-((1S,2S,5S)-2-benzyl-5-hydroxy-4-methylcyclohex-3-en-1-yl)propane-1,2-diol (5168). Among the selected 12 compounds, the metabolites, compound 533 showed the best docking scores. Interestingly, the MD simulation studies for compound 533, the one with the highest docking score, over 100 ns showed its correct binding to SARS-CoV-2 helicase with low energy and optimum dynamics. Finally, MM-PBSA studies showed that 533 bonded favorably to SARS-CoV-2 helicase with a free energy value of -83 kJ/mol. Further, the free energy decomposition study determined the essential amino acid residues that contributed favorably to the binding process. The obtained results give a huge hope to find a cure for COVID-19 through further in vitro and in vivo studies for the selected compounds.