Limits...
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

The ligand–protein interaction analyses of salvianolic acid C with hHMGR.Notes: (A) The overall ribbon structure. (B) The 3D hydrophobicity surface plot at the binding site. (C) The interaction analyses in 2D. (D) The predicted H-bonds between the ligand and the nearby binding site residues.Abbreviations: 2D, two dimensional; 3D, three dimensional; hHMGR, human HMG-CoA reductase.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492635&req=5

f6-dddt-9-3313: The ligand–protein interaction analyses of salvianolic acid C with hHMGR.Notes: (A) The overall ribbon structure. (B) The 3D hydrophobicity surface plot at the binding site. (C) The interaction analyses in 2D. (D) The predicted H-bonds between the ligand and the nearby binding site residues.Abbreviations: 2D, two dimensional; 3D, three dimensional; hHMGR, human HMG-CoA reductase.

Mentions: The detailed ligand–protein interactions of the four compounds can be further analyzed through the view interaction tools DS 4.0. Using Sal C as an example (Figure 6), it was predicted that Sal C fits well in the interface between the two subunits, quite similar to the site occupied by atorvastatin. As shown in Figure 6C and D, its interactions with hHMGR include residues from subunit A (green) and subunit B (red), potentially forming H-bond with Ser B661, Ala A751, Lys B692, and Lys A735. Others are mainly hydrophobic interactions and van der Waals interactions. Basically, the ligand–protein interaction analysis revealed that these molecules occupy similar binding sites as the normal substrate (HMG-CoA) in the catalytic domain and may form hydrogen bonds, electrostatic interactions, and hydrophobic interactions with the residues at the binding site of hHMGR (The ligand–receptor interactions of curcumin and docosanol are shown in Figure S1).


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)

The ligand–protein interaction analyses of salvianolic acid C with hHMGR.Notes: (A) The overall ribbon structure. (B) The 3D hydrophobicity surface plot at the binding site. (C) The interaction analyses in 2D. (D) The predicted H-bonds between the ligand and the nearby binding site residues.Abbreviations: 2D, two dimensional; 3D, three dimensional; hHMGR, human HMG-CoA reductase.
© Copyright Policy
Related In: Results  -  Collection

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

f6-dddt-9-3313: The ligand–protein interaction analyses of salvianolic acid C with hHMGR.Notes: (A) The overall ribbon structure. (B) The 3D hydrophobicity surface plot at the binding site. (C) The interaction analyses in 2D. (D) The predicted H-bonds between the ligand and the nearby binding site residues.Abbreviations: 2D, two dimensional; 3D, three dimensional; hHMGR, human HMG-CoA reductase.
Mentions: The detailed ligand–protein interactions of the four compounds can be further analyzed through the view interaction tools DS 4.0. Using Sal C as an example (Figure 6), it was predicted that Sal C fits well in the interface between the two subunits, quite similar to the site occupied by atorvastatin. As shown in Figure 6C and D, its interactions with hHMGR include residues from subunit A (green) and subunit B (red), potentially forming H-bond with Ser B661, Ala A751, Lys B692, and Lys A735. Others are mainly hydrophobic interactions and van der Waals interactions. Basically, the ligand–protein interaction analysis revealed that these molecules occupy similar binding sites as the normal substrate (HMG-CoA) in the catalytic domain and may form hydrogen bonds, electrostatic interactions, and hydrophobic interactions with the residues at the binding site of hHMGR (The ligand–receptor interactions of curcumin and docosanol are shown in Figure S1).

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