Identification of Nonpeptide CCR5 Receptor Agonists by Structure-based Virtual Screening

Esther Kellenberger,†* Jean-Yves Springael,‡ Marc Parmentier,‡ Muriel Hachet-Haas,§ Jean-Luc Galzi,§ and Didier Rognan†
Bioinformatics of the Drug, CNRS UMR 7175-LC1, F-67400 Illkirch, France, Institut de Recherche Interdisciplinaire en Biologie Humaine et Molculaire (IRIBHM), Universit Libre de Bruxelles, B-1070 Brussels, Belgium, and Dynamics of G Protein-Coupled Receptors, CNRS UMR7175-LC1, F-67400 Illkirch, France
J. Med. Chem., 2007, 50 (6), pp 1294–1303
DOI: 10.1021/jm061389p
Publication Date (Web): February 21, 2007
Copyright © 2007 American Chemical Society
†

 Bioinformatics of the Drug, CNRS UMR7175-LC1.

,
*

 To whom correspondence should be addressed:  Phone:  +33-3-90 24 42 21, fax:  +90 24 43 10, e-mail:  esther.kellenberger@pharma.u-strasbg.fr.

,
‡

 Université Libre de Bruxelles.

,
§

 Dynamics of G Protein-Coupled Receptors, CNRS UMR7175-LC1.

Abstract

Abstract Image

A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its α-helix bundle and to distinguish known CCR5 antagonists from randomly chosen drug-like decoys. In silico screening of a library of 1.6 million commercially available compounds against the CCR5 model by sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit list of 59 compounds, out of which 10 exhibited a detectable binding affinity to the CCR5 receptor. Unexpectedly, most binders tested in a functional assay were shown to be agonists of the CCR5 receptor. A follow-up database query based on similarity to the most potent binders identified three new CCR5 agonists. Despite a moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown to promote efficient receptor internalization, which is a process therapeutically favorable for protection against HIV-1 infection.

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History

  • Published In Issue March 22, 2007
  • Received December 4, 2006

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