Homology model and docking studies on porcine β ₂ adrenoceptor: Description of two binding sites

The affinity of the classical β ₂ adrenoceptor-selective inverse agonist ICI118,551 is notoriously lower for porcine β ₂ adrenoceptors (p ₂βAR) than for human β ₂ adrenoceptors (hβ ₂AR) but molecular mechanisms for this difference are still unclear. Homology 3-D models of pβ ₂AR can be useful in predicting similarities and differences, which might in turn increase the comparative understanding of ligand interactions with the hβ ₂AR. In this work, the pβ ₂AR amino acid sequence was used to carry out homology modeling. The selected pβ ₂AR 3-D structure was structurally and energetically optimized and used as a model for further theoretical study. The homology model of pβ ₂AR has a 3-D structure very similar to the crystal structures of recently studied hβ ₂AR. This was also corroborated by sequence identity, RMSD, Ramachandran map, TM-score and docking results. Upon performing molecular docking simulations with the AutoDock4.0.1 program on pβ ₂AR, it was found that a set of well-known β ₂AR ligands reach two distinct binding sites on pβ ₂AR. Whereas one of these sites is similar to that reported on the hβ ₂AR crystal structure, the other can explain some important experimental observations. Additionally, the theoretical affinity estimated for ICI118,551 closely agrees with affinities estimated from experimental in vitro data. The experimental differences between the human/porcine β ₂ARs in relation to ligand affinity can in part be elucidated by observations in this molecular modeling study.