title: Understanding electrostatic and steric requirements related to hypertensive action of AT(1) antagonists using molecular modeling techniques.
abstract: AT1 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 AT1 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 pIC50 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 AT1 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 AT1 antagonists.
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: da C Silva
authors.forename: Vinicius G
authors.initials: VG
authors.lastname: Maltarollo
authors.forename: Emmanuela Ferreira
authors.initials: EF
authors.lastname: de Lima
authors.forename: Karen Cacilda
authors.initials: KC
authors.lastname: Weber
authors.forename: Kathia M
authors.initials: KM
authors.lastname: Honorio
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D017076:Computer-Aided Design; D015195:Drug Design; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D055672:Static Electricity
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1