Lapachol and (α/β)-lapachone as inhibitors of SARS-CoV-2 main protease (Mpro) and hACE-2: ADME properties, docking and dynamic simulation approaches

Background: Tabebuia impetiginosa is an important medicinal plant rich in lapachol, α‑lapachone, and β‑lapachone known to possess several biological activities. Objective: In this study, we investigated the drug potential of lapachol, α‑lapachone, and β‑lapachone using molecular docking, molecular dynamic (MD), and drug‑likeness properties. Materials and Methods: The computational study was performed using SwissADME software for the determination of the pharmacokinetic properties of the tested compounds. AutoDock Vina and Genetic Optimization for Ligand Docking (GOLD) were used for the docking analysis, and MD simulations were run using Schrodinger’s Desmond Simulation. Results: The three compounds lapachol, α‑lapachone, and β‑lapachone binds to cysteine (Cys)‑histidine (His) catalytic dyad (Cys145 and His41) along with the other residues with, respectively, the following docking score 48.69, 47.06, and 47.79. Against viral entry receptor, human angiotensin‑converting enzyme 2 (hACE‑2), α‑lapachone exhibited the highest GOLD Fitness score complex (54.82) followed by lapachol (42.53) and β‑lapachone and hACE‑2 (38.74) generating several active sites in the target proteins. A 100 ns MDs simulation study revealed the stable conformation of bioactive compounds within the cavity of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) of hACE‑2 protein and main protease (Mpro). From the dynamic study, it was observed that lapachol was tightly bound with catalytic dyad residue Cys145 of Mpro with more than 40% time of simulation, also post‑simulation MM‑GBSA binding free energy (ΔG Bind) revealed the highest energy score (−51.18 ± 5.14 kcal/mol) among the evaluated complex. Moreover, the absorption, distribution, metabolism, and excretion (ADME) properties demonstrated that the investigated compounds passed the pharmacokinetic and drug‑likeness criteria without undesirable effects. Conclusion: The computational study highlighted that these compounds could be highly recommended and developed as part of an effective drug against the SARS‑CoV‑2 virus