Understanding electrostatic and steric requirements related to hypertensive action of AT1 antagonists using molecular modeling techniques

AT(1) receptor is an interesting biological target involved in several important diseases, such as blood hypertension and cardiovascular pathologies. In this study we investigated the main electrostatic and steric features of a series of AT(1) antagonists related to hypertensive activity using structure and ligand-based strategies (docking and CoMFA). The generated 3D model had good internal and external consistency and was used to predict the potency of an external test set. The predicted values of pIC(50) are in good agreement with the experimental results of biological activity, indicating that the 3D model can be used to predict the biological property of untested compounds. The electrostatic and steric CoMFA maps showed molecular recognition patterns, which were analyzed with structure-based molecular modeling studies (docking). The most and the least potent compounds docked into the AT(1) binding site were subjected to molecular dynamics simulations with the aim to verify the stability and the flexibility of the ligand-receptor interactions. These results provided valuable insights on the electronic/structural requirements to design novel AT(1) antagonists.