In silico study of the binding mode of biased agonists of the angiotensin II type 1 receptor (AT1)

AT1 is a G protein‐coupled receptor (GPCR), and the interaction with angiotensin II (AngII) causes vasoconstriction by Gq protein signaling. AT1 activation leads to receptor internalization by β‐arrestin, which can also act as a second messenger. Biased agonists are pharmacologically advantageous because they can antagonize the effects of Gq without interrupting β‐arrestin beneficial effects (cellular growth and survival), however, their binding mode remains unknown. Here, we investigated how biased agonists bind to AT1 using molecular docking and molecular dynamics simulations. AT1 homology model was built based on CXCR4 crystal structure and inserted in a lipid bilayer. The binding mode of five biased agonists (TRV027, TRV023, SI, SII and DVG) and 2 full agonists (AngII and SVdF) was compared. The analysis of interatomic distances showed that biased agonists interact with Trp84, Tyr87, Glu173, Asn174, Cys180 and Tyr292, while SVdF interacts with His183 and Gln187. Ser105, Arg167, Tyr184, Glu185 and Lys199 help positioning both biased and full agonists inside the receptor pocket, not affecting their activation mechanism. Because of the different binding mode, biased agonists cause conformational changes in AT1 that block Gq actions, still keeping β‐arrestin activated.