Molecular dynamics simulations to explore the active/inactive conformers of guinea pig β2 adrenoceptor for the selective design of agonists or antagonists

It is well known that guinea pig β₂ adrenoceptors (Gβ₂ARs) and human β₂ adrenoceptors (Hβ₂ARs) have structural similarity. However, only one conformational state of Gβ₂ARs has been studied – the putative inactive state. As adrenoceptors have a repertoire of conformations, and there is evidence that a certain conformation is stabilised as a ligand approaches, the aim of this study was to build four models of Gβ₂ARs by using putative active/inactive Hβ₂AR conformers as a template. We evaluated the accuracy of these models in regard to the binding mode and affinity values of a set of known β₂AR ligands through docking and molecular dynamics simulations. During docking simulations, ligands reached Gβ₂AR sites similar to those reported for Hβ₂ARs. The greatest differences between conformational states were found in the domains (TM5 and TM6) previously suggested as being key to ligand recognition. The coefficients of determination between experimental and calculated affinity values were near to but less than 0.66 in all cases. The highest values were for agonists on the active models and antagonists on the inactive model. The four Gβ₂AR models proved useful for analysing agonist/antagonist activity. The results suggest that the selection of an adequate model is dependent on the intrinsic activity of a given ligand.