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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

Inhibition on hHMGR enzyme activities by (A) salvianolic acid c, (B) curcumin, and (C) docosanol.Abbreviation: hHMGR, human HMG-CoA reductase.
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f4-dddt-9-3313: Inhibition on hHMGR enzyme activities by (A) salvianolic acid c, (B) curcumin, and (C) docosanol.Abbreviation: hHMGR, human HMG-CoA reductase.

Mentions: After evaluating the docking scores, accessibility, and known functions of the ten compounds, we were left with salvinolic acid C (compound 1), curcumin (compound 3), docosanol (compound 8), and folic acid (compound 10) for further experimental assays. As shown in Figure 4, the results indicated that Sal C, curcumin, and docosanol, can effectively inhibit hHMGR activities. However, folic acid was found to have no inhibitory capability. The IC50 of Sal C, curcumin, and docosanol upon hHMGR activities were further determined to be approximately 8 µM, 4.3 µM, and 250 µM, respectively. These values are much weaker than those of statins which have IC50 values in the nM ranges.


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)

Inhibition on hHMGR enzyme activities by (A) salvianolic acid c, (B) curcumin, and (C) docosanol.Abbreviation: hHMGR, human HMG-CoA reductase.
© Copyright Policy
Related In: Results  -  Collection

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

f4-dddt-9-3313: Inhibition on hHMGR enzyme activities by (A) salvianolic acid c, (B) curcumin, and (C) docosanol.Abbreviation: hHMGR, human HMG-CoA reductase.
Mentions: After evaluating the docking scores, accessibility, and known functions of the ten compounds, we were left with salvinolic acid C (compound 1), curcumin (compound 3), docosanol (compound 8), and folic acid (compound 10) for further experimental assays. As shown in Figure 4, the results indicated that Sal C, curcumin, and docosanol, can effectively inhibit hHMGR activities. However, folic acid was found to have no inhibitory capability. The IC50 of Sal C, curcumin, and docosanol upon hHMGR activities were further determined to be approximately 8 µM, 4.3 µM, and 250 µM, respectively. These values are much weaker than those of statins which have IC50 values in the nM ranges.

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