Journal of Computer-Aided Molecular Design

, Volume 14, Issue 8, pp 753–768

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

  • Nunzia Cinone
  • Hans-Dieter Höltje
  • Angelo Carotti
Article

DOI: 10.1023/A:1008168127539

Cite this article as:
Cinone, N., Höltje, HD. & Carotti, A. J Comput Aided Mol Des (2000) 14: 753. doi:10.1023/A:1008168127539

Abstract

Different classes of Peripheral-type Benzodiazepine Receptor (PBR) ligands were examined and common structural elements were detected and used to develop a rational binding model based on energetically allowed ligand conformations. Two lipophilic regions and one electrostatic interaction site are essential features for high affinity ligand binding, while a further lipophilic region plays an important modulator role. A comparative molecular field analysis, performed over 130 PBR ligands by means of the GRID/GOLPE methodology, led to a PLS model with both high fitting and predictive values (r2 = 0.898, Q2 = 0.761). The outcome from the 3D QSAR model and the GRID interaction fields computed on the putative endogenous PBR ligands DBI (Diazepam Binding Inhibitor) and TTN (Tetracontatetraneuropeptide) was used to identify the amino acids most probably involved in PBR binding. Three amino acids, bearing lipophilic side chains, were detected in DBI (Phe49, Leu47 and Met46) and in TTN (Phe33, Leu31 and Met30) as likely residues underlying receptor binding. Moreover, a qualitative comparison of the molecular electrostatic potentials of DBI, TTN and selected synthetic ligands indicated also similar electronic properties. Convergent results from the modeling studies of synthetic and endogenous ligands suggest a common binding mode to PBRs. This may help the rational design of new high affinity PBR ligands.

DBIGOLPEGRIDmolecular dynamicsperipheral benzodiazepine receptorPBRpharmacophore modelTTN

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Nunzia Cinone
    • 1
  • Hans-Dieter Höltje
    • 2
  • Angelo Carotti
    • 1
  1. 1.Dipartimento Farmaco ChimicoUniversità degli Studi di BariBariItaly
  2. 2.Institute of Pharmaceutical ChemistryHeinrich-Heine-University DüsseldorfDüsseldorfGermany