Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis

• Published in: BMC complementary and alternative medicine Vol. 21; no. 1; p. 1
• Main Authors: Marahatha, Rishab, Basnet, Saroj, Bhattarai, Bibek Raj, Budhathoki, Prakriti, Aryal, Babita, Adhikari, Bikash, Lamichhane, Ganesh, Poudel, Darbin Kumar, Parajuli, Niranjan
• Format: Journal Article
• Language: English
• Published: London BioMed Central 01.01.2021; BioMed Central Ltd; BMC
• Subjects: Alternative medicine; Analysis; Anticholesteremic agents; Arteriosclerosis; Atherosclerosis; Basic research; Bile; Biological products; Biosynthesis; blood serum; Cardiovascular diseases; Chiropractic Medicine; Cholesterol; Coenzyme A; complement; Complementary & Alternative Medicine; Computer applications; computer simulation; computer software; Constraining; Coronary artery disease; Crystal structure; Crystals; Drug development; Drugs; Enzyme inhibition; Enzymes; Gingerol; Gold; heart; Heart diseases; humans; Hydroxymethylglutaryl-CoA reductase; Hypercholesterolemia; Inhibitors; Internal Medicine; Iron compounds; Ligands; Literature reviews; Medicine; Medicine & Public Health; Metabolites; Molecular docking; Natural products; Oxidases; Oxidative stress; Pharmacokinetics; Physical fitness; Physiological aspects; Plant metabolites; prediction; Proteins; Reactive oxygen species; Reductases; Research Article; Secondary metabolites; Software; Statins; stroke; Stroke (Disease); Thiols; Toxicity; Uric acid; Xanthine oxidase; Enzyme inhibition; Natural products; Molecular docking; Cholesterol
• ISSN: 2662-7671; 2662-7671; 1472-6882
• DOI: 10.1186/s12906-020-03162-5

Background Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates’ requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup. Methods Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC 50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software , combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes . In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. Results The molecular docking of amentoflavone (GOLD score 70.54, ∆G calc. = − 10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ∆G calc. = − 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6′ → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use. Conclusion This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.