Ligand-supported homology modeling of the human angiotensin II type 1 (AT1) receptor: Insights into the molecular determinants of telmisartan binding

• Published in: Proteins, structure, function, and bioinformatics Vol. 65; no. 4; pp. 824 - 842
• Main Authors: Patny, Akshay, Desai, Prashant V., Avery, Mitchell A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2006
• Subjects: Amino Acid Sequence; Angiotensin II Type 1 Receptor Blockers - chemistry; Angiotensin II Type 1 Receptor Blockers - metabolism; Animals; AT1 receptor; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Benzoates - chemistry; Benzoates - metabolism; Binding Sites; Cattle; docking; drug design; GPCR; homology modeling; Humans; Ligands; losartan; Models, Molecular; molecular dynamics; Molecular Sequence Data; Protein Structure, Tertiary; Receptor, Angiotensin, Type 1 - chemistry; Receptor, Angiotensin, Type 1 - metabolism; Receptors, G-Protein-Coupled - metabolism; Rhodopsin - chemistry; Rhodopsin - metabolism; Sequence Alignment; Structural Homology, Protein; telmisartan
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.21196

Angiotensin II type 1 (AT1) receptor belongs to the super‐family of G‐protein‐coupled receptors, and antagonists of the AT1 receptor are effectively used in the treatment of hypertension. To understand the molecular interactions of these antagonists, such as losartan and telmisartan, with the AT1 receptor, a homology model of the human AT1 (hAT1) receptor with all connecting loops was constructed from the 2.6 Å resolution crystal structure (PDB i.d., 1L9H) of bovine rhodopsin. The initial model generated by MODELLER was subjected to a stepwise ligand‐supported model refinement. This protocol involved initial docking of non‐peptide AT1 antagonists in the putative binding site, followed by several rounds of iterative energy minimizations and molecular dynamics simulations. The final model was validated based on its correlation with several structure‐activity relationships and site‐directed mutagenesis data. The final model was also found to be in agreement with a previously reported AT1 antagonist pharmacophore model. Docking studies were performed for a series of non‐peptide AT1 receptor antagonists in the active site of the final hAT1 receptor model. The docking was able to identify key molecular interactions for all the AT1 antagonists studied. Reasonable correlation was observed between the interaction energy values and the corresponding binding affinities of these ligands, providing further validation for the model. In addition, an extensive unrestrained molecular dynamics simulation showed that the docking‐derived bound pose of telmisartan is energetically stable. Knowledge gained from the present studies can be used in structure‐based drug design for developing novel ligands for the AT1 receptor. Proteins 2006. © 2006 Wiley‐Liss, Inc.