Discovery of Novel Inhibitors of HMG-CoA Reductase Using Bioactive Compounds Isolated From Cochlospermum Species Through Computational Methods: Virtual Screening and Algorithm Validation Study

Abstract

Background: Cholesterol biosynthesis is a critical pathway in cellular metabolism, with 3- hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzing its committed step. The inhibition of HMGR has been widely explored as a therapeutic target for managing hypercholesterolemia, and statins are the most commonly used competitive inhibitors. However, the search for novel, natural inhibitors of HMGR is still a vital area of research, especially in light of the adverse effects of the prolonged use of statins. Cochlospermum planchonii and Cochlospermum tinctorium are medicinal plants traditionally used in West Africa to treat metabolic disorders, including dyslipidemia, but the specific bioactive compounds responsible for these effects are currently poorly characterized. Objective: This study aims to investigate the potential of the phytochemicals isolated from Cochlospermum planchonii and Cochlospermum tinctorium as novel, natural inhibitors of human HMGR, using molecular docking techniques. Methods: A total of 84 phytochemicals from two species of Cochlospermum as reported in the literature, were evaluated as potential inhibitors of HMGR. Using DataWarrior software, their drug-likeness and ADMET properties were screened in accordance with Lipinski’s Rule of Five. 32 compounds that met the criteria were docked on PyRx against the HMG-binding site of HMGR, together with its native ligand atorvastatin and 6 known statins serving as control ligands. Results: The docking analysis of the best binding modes of the compounds showed that 10 (31.3%) of the 32 phytochemicals demonstrated strong binding affinities and interactions with the HMG-binding pocket (residues 682-694) of the enzyme, with their binding energy (ΔG) scores ranging from -4.6 to -6.0 kcal/mol, comparable to or exceeding the range of those of statins (-4.6 to -5.7 kcal/mol). The range of their docking scores (-13.272 to -32.103) also compared favourably with those of statins (-25.939 to -36.584). One of the lead compounds, 3-O-methylellagic acid (ID_13915428) demonstrated stronger and more substantial binding interactions (26) with the HMG-binding pocket residues of the enzyme than any other compounds, including statins. Using one-way analysis of variance (ANOVA), the mean and standard deviation of the binding affinity scores of the phytochemicals and statins (9 replicates each) were significantly different at P