Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening

• Published in: Drug design, development and therapy Vol. 9; no. default; pp. 3313 - 3324
• Main Authors: Lin, Shih-Hung, Huang, Kao-Jean, Weng, Ching-Feng, Shiuan, David
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2015; Taylor & Francis Ltd; Dove Medical Press
• Subjects: Alcohols; Alkenes - chemistry; Alkenes - pharmacology; Apoptosis; Arteriosclerosis; Atherosclerosis; Binding Sites; Biosynthesis; Cancer therapies; Cardiovascular disease; Chinese medicine; Cholesterol; Cloning; Coenzyme A; Curcumin; Curcumin - chemistry; Curcumin - pharmacology; Data banks; Databases, Protein; Dose-Response Relationship, Drug; Drug development; Drug Discovery - methods; Drugs; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - metabolism; Drugs, Chinese Herbal - pharmacology; Drugs, Chinese Herbal - toxicity; E coli; Enzyme inhibitors; Enzymes; Excretion; Feasibility Studies; Hep G2 Cells; Herbal medicine; Humans; Hydroxymethylglutaryl CoA Reductases - chemistry; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA reductase; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - toxicity; Identification and classification; Inhibitors; Kinases; Ligands; Lipophilic; Metabolism; Methods; Molecular Docking Simulation; Natural products; Original Research; Pharmaceutical research; Polyphenols; Polyphenols - chemistry; Polyphenols - pharmacology; Protein Binding; Protein Conformation; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Screening; Side effects; Software; Statins; Structure-Activity Relationship; Toxicity; Toxicology; Traditional Chinese medicine; United States > US; China; Taiwan; salvianolic acid C; virtual screening; HMG-CoA reductase; curcumin
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S84641

Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening.