Applying in silico Tools to the Discovery of Novel CXCR4 Inhibitors

Violeta I. Pérez-Nueno (1) , David Ritchie (1)

1 ORPAILLEUR - Knowledge representation, reasonning

The process of HIV entry begins with the binding of the viral envelope glycoprotein gp120 to both the CD4 receptor and one of the CXCR4 or CCR5 chemokine coreceptors. There is currently considerable interest in developing novel ligands which can bind to these coreceptors and hence block virus-cell fusion. This article reviews the use of different in silico structure-based and ligand-based virtual screening (VS) tools for the discovery of potential HIV entry inhibitors for the CXCR4 receptor. More specifically, it discusses homology modelling, de novo design, docking, QSAR analyses, pharmacophore modelling, and similarity searches. Results from retrospective VS of a library of known CXCR4 inhibitors taken from the literature and from prospective VS of a combinatorial virtual library are reviewed. The structures of active compounds found by these approaches, as well as CXCR4 inhibitors currently in development are also discussed.

Mots clés: virtual screening; HIV; CXCR4/CCR5 inhibitors; GPCRs; homology modelling; docking; shape matching; pharmacophore; QSAR; similarity search; de novo design

Domaines: Bio-informatique [q-bio.QM]; Bio-Informatique, Biologie Systémique [q-bio.QM]

Violeta I. Pérez-Nueno, David Ritchie. Applying in silico Tools to the Discovery of Novel CXCR4 Inhibitors. Drug Development Research, 2010, ⟨10.1002/ddr.20406⟩. ⟨inria-00550645⟩