title: Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening.
abstract: 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.
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Shih-Hung
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China ; Development Center of Biotechnology, Taipei, Taiwan, Republic of China.
authors.forename: Kao-Jean
authors.initials: KJ
authors.lastname: Huang
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Weng
authors.affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.
authors.forename: David
authors.initials: D
authors.lastname: Shiuan
mesh_terms: D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D030562:Databases, Protein; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005240:Feasibility Studies; D056945:Hep G2 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D008024:Ligands; D062105:Molecular Docking Simulation; D059808:Polyphenols / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D001572:Benzofurans
chemical_list: D000475:Alkenes; D003474:Curcumin; D004365:Drugs, Chinese Herbal; D006903:Hydroxymethylglutaryl CoA Reductases; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008024:Ligands; D059808:Polyphenols; D011994:Recombinant Proteins; C553220:HMGCR protein, human; C000597819:salvianolic acid C; D001572:Benzofurans
keywords: HMG-CoA reductase; curcumin; salvianolic acid C; virtual screening