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

Aim: Both endothelin ETA receptor antagonists and angiotensin AT(1) receptor antagonists lower blood pressure in hypertensive patients. A dual AT(1) and ETA 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 ETA 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 ETA 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 ETA receptor; addition of a trimethylpyrrolidinone to compound 9 significantly reduced its activity against AT(1) receptor but significantly increased its activity against ETA 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 ETA 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 ETA receptor antagonists. Conclusion: This study may provide some insights into the development of novel potent dual ETA and AT(1) receptor antagonists. As a result, five compounds are found to be the best dual antagonists against AT(1)R and ETA receptors.