Mechanism of Inhibition of Cholesteryl Ester Transfer Protein by Small Molecule Inhibitors.
Cholesteryl ester transfer protein (CETP) facilitates the bidirectional exchange of cholesteryl esters and triglycerides between high-density lipoproteins and low- or very low-density lipoproteins. Recent studies have shown that the impairment of lipid exchange processes of CETP can be an effective strategy for the treatment of cardiovascular diseases (CVDs). Understanding the molecular mechanism of CETP inhibition has, therefore, attracted tremendous attention in recent past. In this study, we explored the detailed mechanism of CETP inhibition by a series of recently reported small molecule inhibitors that are currently under preclinical testing. Our results from molecular dynamics simulations and protein-ligand docking studies suggest that the hydrophobic interactions between the CETP core tunnel residues and inhibitor moieties play a pivotal role, and physical occlusion of the CETP tunnel by these small molecules is the primary mechanism of CETP inhibition. Interestingly, bound inhibitors were found to increase the plasticity of CETP, which was explained by principal component analysis that showed a larger space of sampling of CETP C-domain due to inhibitor binding. The atomic-level details presented here could help accelerate the structure-based drug-discovery processes targeting CETP for CVD therapeutics.
Bhupat and Jyoti Mehta School of Biosciences and Department of Biotechnology, Indian Institute of Technology Madras , Chennai 600036, India.
Venkat R
VR
Chirasani
Bhupat and Jyoti Mehta School of Biosciences and Department of Biotechnology, Indian Institute of Technology Madras , Chennai 600036, India.
Revathi
R
Sankar
Bhupat and Jyoti Mehta School of Biosciences and Department of Biotechnology, Indian Institute of Technology Madras , Chennai 600036, India.
Sanjib
S
Senapati
D000924:Anticholesteremic Agents / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry*; D001596:Benzylamines / Q000737:chemistry*; D001665:Binding Sites; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002788:Cholesterol Esters / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D023303:Oxazolidinones / Q000737:chemistry*; D025341:Principal Component Analysis; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D054852:Small Molecule Libraries / Q000737:chemistry*; D013379:Substrate Specificity; D013816:Thermodynamics; D014280:Triglycerides / Q000737:chemistry
D000924:Anticholesteremic Agents; C000605770:BMS-795311; D001549:Benzamides; D001596:Benzylamines; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D023303:Oxazolidinones; D054852:Small Molecule Libraries; D014280:Triglycerides; C530884:anacetrapib