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

Lin SH, Huang KJ, Weng CF, Shiuan D - Drug Des Devel Ther (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus

Potential cytotoxic activities of the selected compounds: salvianolic acid C (gray), curcumin (blank column), and docosanol (horizontal lines).Note: atorvastatin (black) was used as the positive control.
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f5-dddt-9-3313: Potential cytotoxic activities of the selected compounds: salvianolic acid C (gray), curcumin (blank column), and docosanol (horizontal lines).Note: atorvastatin (black) was used as the positive control.

Mentions: The potential cytotoxic effects of Sal C, curcumin, and docosanol on HepG2 cells were then examined by the MTT assay. As shown in Figure 5, atorvastatin, such a well-known hypocholesterolemic drug, exhibited a pronounced concentration-dependent cytotoxicity effect (CC50 [50% cytotoxic concentration] near 100 µM). Curcumin retarded the HepG2 growth rate even more effectively (CC50 near 42 µM).24 On the other hand, Sal C was found to have no cytotoxic effect under the testing concentration range, and even enhanced the cell viability slightly, while docosanol had a milder cytotoxic effect.


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

Lin SH, Huang KJ, Weng CF, Shiuan D - Drug Des Devel Ther (2015)

Potential cytotoxic activities of the selected compounds: salvianolic acid C (gray), curcumin (blank column), and docosanol (horizontal lines).Note: atorvastatin (black) was used as the positive control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492635&req=5

f5-dddt-9-3313: Potential cytotoxic activities of the selected compounds: salvianolic acid C (gray), curcumin (blank column), and docosanol (horizontal lines).Note: atorvastatin (black) was used as the positive control.
Mentions: The potential cytotoxic effects of Sal C, curcumin, and docosanol on HepG2 cells were then examined by the MTT assay. As shown in Figure 5, atorvastatin, such a well-known hypocholesterolemic drug, exhibited a pronounced concentration-dependent cytotoxicity effect (CC50 [50% cytotoxic concentration] near 100 µM). Curcumin retarded the HepG2 growth rate even more effectively (CC50 near 42 µM).24 On the other hand, Sal C was found to have no cytotoxic effect under the testing concentration range, and even enhanced the cell viability slightly, while docosanol had a milder cytotoxic effect.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus