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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

Identification of the ligand-binding sites of hHMGR.Notes: (A) The tetrameric structure of hHMGR (PDB 1HWK). (B) The dimeric hHMGRs displaying subunit a (red), subunit B (green), and atorvastatin (yellow). (C) The active site from PDB site record. (D) analysis of the ligand–receptor interactions.Abbreviations: hHMGR, human HMG-CoA reductase; PDB, Protein Data Bank.
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f1-dddt-9-3313: Identification of the ligand-binding sites of hHMGR.Notes: (A) The tetrameric structure of hHMGR (PDB 1HWK). (B) The dimeric hHMGRs displaying subunit a (red), subunit B (green), and atorvastatin (yellow). (C) The active site from PDB site record. (D) analysis of the ligand–receptor interactions.Abbreviations: hHMGR, human HMG-CoA reductase; PDB, Protein Data Bank.

Mentions: The 3D structure of hHMGR (PDB 1HWK) was chosen as the molecular target of the present study. It is a tetramer of hHMGR proteins complexed with four atorvastatin molecules that are located at the interfaces between two adjacent monomers (Figure 1A and B). As shown in Figure 1C and D, the binding site was surrounded by the key residues Arg A590, Ser A661, Val A683, Ser A684, Asp A690, and Lys A691 from the subunit A (red); Glu B559, Cys B561, Leu B562, Ala B564, Ser B565, His B752, Lys B735, Asn B755, Leu B853, and Ala B856 from the subunit B (green) of the two adjacent hHMGR monomers.10 To facilitate the docking process, the binding sites were identified by using the tools of DS 3.5, either based on the cavities of the receptor or through the PDB site record (Figure 1C). To evaluate the feasibility of docking parameters, we selected five known statinlike molecules with known IC50 (half maximal inhibitory concentration) values against hHMGR (Figure 2) as a test kit. As shown in Table 1, they were successfully docked into the receptor-binding site with good docking scores, confirming that the –PMF (potential of mean force) scoring function is more feasible and the docking parameters were set properly. Then we went on to screen the TCM database (containing approximately 30,000 pure compounds) and found that only 4,099 received docking scores. Among them, 561 compounds exhibited –PMF scores higher than 70, comparable with the scores of the known statins.


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)

Identification of the ligand-binding sites of hHMGR.Notes: (A) The tetrameric structure of hHMGR (PDB 1HWK). (B) The dimeric hHMGRs displaying subunit a (red), subunit B (green), and atorvastatin (yellow). (C) The active site from PDB site record. (D) analysis of the ligand–receptor interactions.Abbreviations: hHMGR, human HMG-CoA reductase; PDB, Protein Data Bank.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-3313: Identification of the ligand-binding sites of hHMGR.Notes: (A) The tetrameric structure of hHMGR (PDB 1HWK). (B) The dimeric hHMGRs displaying subunit a (red), subunit B (green), and atorvastatin (yellow). (C) The active site from PDB site record. (D) analysis of the ligand–receptor interactions.Abbreviations: hHMGR, human HMG-CoA reductase; PDB, Protein Data Bank.
Mentions: The 3D structure of hHMGR (PDB 1HWK) was chosen as the molecular target of the present study. It is a tetramer of hHMGR proteins complexed with four atorvastatin molecules that are located at the interfaces between two adjacent monomers (Figure 1A and B). As shown in Figure 1C and D, the binding site was surrounded by the key residues Arg A590, Ser A661, Val A683, Ser A684, Asp A690, and Lys A691 from the subunit A (red); Glu B559, Cys B561, Leu B562, Ala B564, Ser B565, His B752, Lys B735, Asn B755, Leu B853, and Ala B856 from the subunit B (green) of the two adjacent hHMGR monomers.10 To facilitate the docking process, the binding sites were identified by using the tools of DS 3.5, either based on the cavities of the receptor or through the PDB site record (Figure 1C). To evaluate the feasibility of docking parameters, we selected five known statinlike molecules with known IC50 (half maximal inhibitory concentration) values against hHMGR (Figure 2) as a test kit. As shown in Table 1, they were successfully docked into the receptor-binding site with good docking scores, confirming that the –PMF (potential of mean force) scoring function is more feasible and the docking parameters were set properly. Then we went on to screen the TCM database (containing approximately 30,000 pure compounds) and found that only 4,099 received docking scores. Among them, 561 compounds exhibited –PMF scores higher than 70, comparable with the scores of the known statins.

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