Identification of non-peptide CCR5 receptor agonists by structure-based virtual screening

A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its !-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 (druglikeness, 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 non-peptide ligands for the CCR5 receptor, one of the agonist was shown to promote efficient receptor internalization, which is a process therapeutically favorable for protection against HIV-1 infection.

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