Identification of nonpeptide 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 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.
Kellenberger
Esther
E
Bioinformatics of the Drug, CNRS UMR 7175-LC1, F-67400 Illkirch, France. esther.kellenberger@pharma.u-strasbg.fr
Springael
Jean-Yves
JY
Parmentier
Marc
M
Hachet-Haas
Muriel
M
Galzi
Jean-Luc
JL
Rognan
Didier
D
D000595:Amino Acid Sequence; D065100:CCR5 Receptor Antagonists; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011724:Pyridazines / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000737:chemistry; D019713:Receptors, CCR5 / Q000819:agonists* / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014230:Triazoles / Q000737:chemistry
D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D010880:Piperidines; D011724:Pyridazines; D011759:Pyrrolidines; D011799:Quinazolines; D019713:Receptors, CCR5; D014230:Triazoles