TY - JOUR
T1 - Molecular dynamics simulations to explore the active/inactive conformers of guinea pig β2adrenoceptor for the selective design of agonists or antagonists
AU - Segura-Cabrera, A.
AU - García-Pérez, C. A.
AU - Ciprés-Flores, F. J.
AU - Cuevas-Hernández, R. I.
AU - Trujillo-Ferrara, J. G.
AU - Correa-Basurto, J.
AU - Soriano-Ursúa, M. A.
N1 - Publisher Copyright:
© 2014 Taylor & Francis.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - It is well known that guinea pig β2adrenoceptors (Gβ2ARs) and human β2adrenoceptors (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.
AB - It is well known that guinea pig β2adrenoceptors (Gβ2ARs) and human β2adrenoceptors (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.
KW - GPCR-2 adrenergic receptor
KW - guinea pig
KW - intrinsic activity
KW - molecular dynamics
UR - http://www.scopus.com/inward/record.url?scp=84907581109&partnerID=8YFLogxK
U2 - 10.1080/08927022.2013.857771
DO - 10.1080/08927022.2013.857771
M3 - Artículo
SN - 0892-7022
VL - 40
SP - 1244
EP - 1254
JO - Molecular Simulation
JF - Molecular Simulation
IS - 15
ER -