Journal of Computer-Aided Molecular Design

, Volume 17, Issue 11, pp 785–796 | Cite as

Peroxisome Proliferator-Activated Receptors target family landscape: A chemometrical approach to ligand selectivity based on protein binding site analysis

  • Bernard Pirard

Abstract

The Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear receptors which over the last couple of years have been the focus of considerable research efforts aiming to identify compounds with well-defined selectivity profiles for the treatment of metabolic diseases. The ligand binding domains (LBD) of the three known PPAR subtypes exhibit between 60 and 70% sequence identity. To gain insight into the structural determinants of selectivity for the PPAR subtypes, a set of 13 crystal structures of PPAR LBD were classified, using the GRID/CPCA approach. As a result, nearly all of the crystal structures of each different PPAR subtype were found clustered in different regions of the CPCA score plots, and hydrophobic as well as steric interactions were identified as the major determinants of PPAR subtypes selectivity. Furthermore, interpretation of the GRID/CPCA model in structural terms led to the identification of LBD regions which could be targeted to improve the selectivity for a given PPAR subtype. Our findings are consistent with published structure–activity relationships for PPAR ligands as well as with site-directed mutagenesis results.

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Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Bernard Pirard
    • 1
  1. 1.Aventis Pharma Deutschland GmbH, DI&A Chemistry, Computational ChemistryFrankfurt am MainGermany

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