Ligand Binding Determinants for Angiotensin II Type 1 Receptor from Computer Simulations

The ligand binding determinants for the angiotensin II type 1 receptor (AT1R), a G protein-coupled receptor (GPCR), have been characterized by means of computer simulations. As a first step, a pharmacophore model of various known AT1R ligands exhibiting a wide range of binding affinities was generated. Second, a structural model of AT1R was built making use of the growing set of crystal structures of GPCRs, which was further used for the docking of the AT1R ligands based on the devised pharmacophore model. Next, ligand-receptor-lipid bilayer systems were studied by means of molecular dynamics (MD) simulations. Overall, the present study has permitted, combining the pharmacophore model with binding free energy calculations obtained from the MD simulations, to propose the molecular mechanisms by which sartans interact with AT1R.