Identification of Nonpeptide CCR5 Receptor Agonists by Structure-based Virtual Screening
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- 作者：Esther Kellenberger ; Jean-Yves Springael ; Marc Parmentier ; Muriel Hachet-Haas ; Jean-Luc Galzi ; and ; Didier Rognan
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：March 22, 2007
- 年：2007
- 卷：50
- 期：6
- 页码：1294 - 1303
- 全文大小：531K
- 年卷期：v.50,no.6(March 22, 2007)
- ISSN：1520-4804
文摘
A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiaritiesof 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 modelby sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit listof 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-updatabase query based on similarity to the most potent binders identified three new CCR5 agonists. Despitea moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown topromote efficient receptor internalization, which is a process therapeutically favorable for protection againstHIV-1 infection.
-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 modelby sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit listof 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-updatabase query based on similarity to the most potent binders identified three new CCR5 agonists. Despitea moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown topromote efficient receptor internalization, which is a process therapeutically favorable for protection againstHIV-1 infection.