ALPHA-1-ADRENOCEPTOR SUBTYPE SELECTIVITY - MOLECULAR MODELING AND THEORETICAL QUANTITATIVE STRUCTURE-AFFINITY RELATIONSHIPS

This study constitutes a preliminary rationalization, at the molecular level, of antagonist selectivity towards the three cloned alpha 1-adr energic receptor (alpha 1-AR) subtypes. Molecular dynamics simulations allowed a structural/dynamics analysis of the seven alpha-helix-bundl e models of the bovine alpha 1a-, hamster alpha 1b-, and rat alpha 1d- AR subtypes. The results showed that the transmembrane domains of thes e subtypes have different dynamic behaviours and different topographie s of the binding sites, which are mainly constituted by conserved resi dues. In particular, the alpha 1a-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 isolat ed receptors are consistent with the binding affinities of the 16 anta gonists tested towards the three cloned alpha 1a-AR subtypes. Moreover , the theoretical quantitative structure-affinity relationships obtain ed from the antagonist-receptor interaction models further corroborate s the hypothesis that selectivity towards one preferential subtype is mainly modulated by receptor and/or ligand distortion energies. In oth er words, subtype selectivity seems to be mainly guided by the dynamic complementarity (induced fit) between ligand and receptor. On the bas is of the quantitative models presented it is possible to predict both affinities and selectivities of putative alpha 1-AR ligands as well a s to estimate the theoretical alpha 1-AR subtype affinities and select ivities of existing antagonists. (C) 1997 Elsevier Science Ltd.