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 ET_A receptor antagonists and angiotensin AT₁ receptor antagonists lower blood pressure in hypertensive patients. A dual AT₁ 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 AT₁ 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 AT₁ 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 AT₁ 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 AT₁ 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 AT₁ and ET_A receptor antagonists.

Conclusion:

This study may provide some insights into the development of novel potent dual ET_A and AT₁ receptor antagonists. As a result, five compounds are found to be the best dual antagonists against AT₁R and ET_A receptors.