Computational exploration of Withania coagulans-derived natural inhibitors targeting HMG-CoA reductase: A pharmacokinetic, docking and molecular dynamics study for cholesterol regulation in Mus musculus

Background: Hypercholesterolemia is a major modifiable risk factor for cardiovascular disease, largely driven by excessive activity of 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), the rate-limiting enzyme in cholesterol biosynthesis. Although statins are effective inhibitors of this enzyme, their long-term use is often limited by their adverse effects. This has encouraged the search for safer, plant-derived alternatives. Withania coagulans, a medicinal plant rich in withanolides, has demonstrated lipid-lowering potential; however, its molecular interactions with Hmgcr remain insufficiently explored. Objectives: This study aimed to identify and characterize bioactive compounds from Withania coagulans as potential natural inhibitors of Hmgcr in Mus musculus, using an integrated in silico strategy. Methods: A validated three-dimensional model of Mus musculus Hmgcr was generated using homology modeling. Twenty bioactive compounds from Withania coagulans, along with standard statins, were screened using molecular docking and ADMET profiling, following Lipinski’s rule of five. High-ranking complexes were further explored using MM/PBSA and MM/GBSA binding-free energy calculations. Molecular dynamics simulations (100 ns) were performed for top-ranked selected ligand–protein complexes to assess their structural stability and interaction persistence under physiologically relevant conditions. Results: Several Withania coagulans compounds demonstrated strong binding affinities toward the Hmgcr active site, in some cases comparable to or exceeding those of standard statins. The key interactions involved conserved catalytic residues, such as Tyr516, Met533, Ile535, Ile761, Pro812 and Gln813. Molecular dynamics analyses revealed stable complexes with low RMSD fluctuations and minimal active site flexibility, confirming sustained ligand binding. ADMET predictions suggested favorable oral absorption and acceptable drug-like properties for the leading compounds. Conclusion: This study highlights Withania coagulans as a promising source of natural Hmgcr inhibitors. The identified compounds exhibited stable binding, favorable pharmacokinetic profiles, and mechanistic similarity to established statins, supporting their potential for further experimental validation as cholesterol-lowering agents.