Discovery of Novel Inhibitors of HMG-CoA Reductase Using Bioactive Compounds Isolated From Cochlospermum Species Through Computational Methods: Virtual Screening and Algorithm Validation Study
Toba Isaac Olatoye · JMIRx Bio · 2025
Abstract Background Cholesterol biosynthesis is a critical pathway in cellular metabolism, with 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) catalyzing its committed step. HMGR inhibition 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 HMGR inhibitors remains a vital area of research, due to the adverse effects associated with long-term statin use. Cochlospermum planchonii and Cochlospermum tinctorium are West African medicinal plants traditionally used to treat metabolic disorders, including dyslipidemia. Despite their usefulness, the specific bioactive compounds responsible for these effects are currently poorly characterized, justifying further investigations. Objective This study investigates the potential of phytochemicals from Cochlospermum planchonii and Cochlospermum tinctorium as natural inhibitors of human HMGR using molecular docking techniques. Methods A total of 84 phytochemicals from 2 species of Cochlospermum as reported in literature, were evaluated as potential inhibitors of HMGR. Using DataWarrior software, their drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties were screened in accordance with Lipinski’s Rule of Five. The 32 compounds that met the criteria were docked on PyRx against the HMG-binding site of HMGR, alongside atorvastatin (native ligand) and 6 known statins, which served as control ligands. Results Docking analysis of their two best binding modes showed that 10 (31.3%) out of the 32 screened phytochemicals demonstrated strong binding affinities and interactions with the HMG-binding pocket (residues 682‐694) of HMGR, with binding energy (ΔG) scores ranging from −4.6 to −6.0 kcal/mol, comparable to or exceeding those of statins (−4.6 to −5.7 kcal/mol). Their docking scores (−13.272 to −32.103) also compared favorably with those of statins (−25.939 to −36.584). Interestingly, 3-O-methylellagic acid (ID_13915428) demonstrated the strongest interaction, forming 26 binding interactions with the HMG-binding pocket residues, more than any compound, including statins. One-way ANOVA of the mean and SEM of the binding affinity scores for the phytochemicals and statins (9 replicates each) indicated a statistically significant difference at P <.05 (total sample size n=153; actual P =.0001). Conclusions This study is the first to virtually screen and identify specific bioactive compounds isolated from Cochlospermum planchonii and Cochlospermum tinctorium with potential cholesterol-lowering effects in humans. The findings not only support the traditional use of these plants in West Africa to manage dyslipidemia and other ailments, but also present the phytochemicals as promising drug candidates for further optimization as natural inhibitors of HMGR. However, while this study provides valuable computational insights into the molecular interactions of the compounds with HMGR, further advanced computational, in vitro, and in vivo studies are still necessary to validate their inhibitory potential and therapeutic applications.