Molecular modeling, quantum polarized ligand docking and structure-based 3D-QSAR analysis of the imidazole series as dual AT1 and ETA receptor antagonists

Abstract

Aim: Both endothelin ET A receptor antagonists and angiotensin AT 1 receptor antagonists lower blood pressure in hypertensive patients. A dual AT 1 and ET A receptor antagonist may be more efficacious antihypertensive drug. In this study we identified the mode and mechanism of binding of imidazole series of compounds as dual AT 1 and ET A receptor antagonists. Methods: Molecular modeling approach combining quantum-polarized ligand docking (QPLD), MM/GBSA free-energy calculation and 3D-QSAR analysis was used to evaluate 24 compounds as dual AT 1 and ET A receptor antagonists and to reveal their binding modes and structural basis of the inhibitory activity. Pharmacophore-based virtual screening and docking studies were performed to identify more potent dual antagonists. Results: 3D-QSAR models of the imidazole compounds were developed from the conformer generated by QPLD, and the resulting models showed a good correlation between the predicted and experimental activity. The visualization of the 3D-QSAR model in the context of the compounds under study revealed the details of the structure-activity relationship: substitution of methoxymethyl and cyclooctanone might increase the activity against AT 1 receptor, while substitution of cyclohexone and trimethylpyrrolidinone was important for the activity against ET A receptor; addition of a trimethylpyrrolidinone to compound 9 significantly reduced its activity against AT 1 receptor but significantly increased its activity against ET A receptor, which was likely due to the larger size and higher intensities of the H-bond donor and acceptor regions in the active site of ET A receptor. Pharmacophore-based virtual screening followed by subsequent Glide SP, XP, QPLD and MM/GBSA calculation identified 5 potential lead compounds that might act as dual AT 1 and ET A receptor antagonists. Conclusion: This study may provide some insights into the development of novel potent dual ET A and AT 1 receptor antagonists. As a result, five compounds are found to be the best dual antagonists against AT 1 R and ET A receptors.

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