Development of a unique 3D interaction model of endogenous and synthetic peripheral benzodiazepine receptor ligands

Different classes of Peripheral-type Benzodiazepine Receptor (PBR) ligands were examined and common structural elements were detected and used to deve lop a rational binding model based on energetically allowed ligand conforma tions. Two lipophilic regions and one electrostatic interaction site are es sential features for high affinity ligand binding, while a further lipophil ic region plays an important modulator role. A comparative molecular field analysis, performed over 130 PBR ligands by means of the GRID/GOLPE methodo logy, led to a PLS model with both high fitting and predictive values (r(2) = 0.898, Q(2) = 0.761). The outcome from the 3D QSAR model and the GRID in teraction fields computed on the putative endogenous PBR ligands DBI (Diaze pam Binding Inhibitor) and TTN (Tetracontatetraneuropeptide) was used to id entify the amino acids most probably involved in PBR binding. Three amino a cids, bearing lipophilic side chains, were detected in DBI (Phe49, Leu47 an d Met46) and in TTN (Phe33, Leu31 and Met30) as likely residues underlying receptor binding. Moreover, a qualitative comparison of the molecular elect rostatic potentials of DBI, TTN and selected synthetic ligands indicated al so similar electronic properties. Convergent results from the modeling stud ies of synthetic and endogenous ligands suggest a common binding mode to PB Rs. This may help the rational design of new high affinity PBR ligands.