α1-Adrenoceptor subtype selectivity: Molecular modelling and theoretical quantitative structure—affinity relationships Original Research Article

This study constitutes a preliminary rationalization, at the molecular level, of antagonist selectivity towards the three cloned α1-adrenergic receptor (α1-AR) subtypes. Molecular dynamics simulations allowed a structural/dynamics analysis of the seven α-helix-bundle models of the bovine α1a-, hamster α1b-, and rat α1d-AR subtypes. The results showed that the transmembrane domains of these subtypes have different dynamic behaviours and different topographies of the binding sites, which are mainly constituted by conserved residues. In particular, the α1a-AR binding site is more flexible and topographically different with respect to the other two subtypes. The results of the theoretical structural/dynamics analysis of the isolated receptors are consistent with the binding affinities of the 16 antagonists tested towards the three cloned α1-AR subtypes. Moreover, the theoretical quantitative structure-affinity relationships obtained from the antagonist-receptor interaction models further corroborates the hypothesis that selectivity towards one preferential subtype is mainly modulated by receptor and/or ligand distortion energies. In other words, subtype selectivity seems to be mainly guided by the dynamic complementarity (induced fit) between ligand and receptor. On the basis of the quantitative models presented it is possible to predict both affinities and selectivities of putative α1-AR ligands as well as to estimate the theoretical α1-AR subtype affinities and selectivities of existing antagonists.