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Identification of nonpeptide CCR5 receptor agonists by structure-based virtual screening.

Kellenberger E, Springael JY, Parmentier M, Hachet-Haas M, Galzi JL, Rognan D

Bioinformatics of the Drug, CNRS UMR 7175-LC1, F-67400 Illkirch, France. esther.kellenberger@pharma.u-strasbg.fr

A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its alpha-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.

Published 15 March 2007 in J Med Chem, 50(6): 1294-303.
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