Use of the X-ray structure of the Beta2-adrenergic receptor for drug discovery
- 作者：Sid Topiol ; Michael Sabio
- 关键词：Beta2-adrenergic receptor ; X-ray structure ; High-throughput docking ; Computer-aided design ; GPCR ; Molecular modeling ; Corazolol ; Carvedilol ; Propranolol ; Butoxamine ; Timolol ; Celiprolol ; Dichloroisoprenaline
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2008
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：1 March 2008
- 卷：18
- 期：5
- 页码：1598-1602
- 文件大小：630 K
摘要
The recently reported X-ray structure of the Beta2-adrenergic receptor, the first reported crystal structure of a ligand-mediated GPCR, is used to explore its utility in computer-aided drug design. Validations were conducted with known beta blockers. This was followed by high-throughput docking studies with proprietary and commercial databases to further validate the X-ray structure’s usefulness as a design tool and to explore the potential for discovery of novel chemical classes acting as Beta2 inhibitors. Our results include the finding of ligands with traditional beta-blocker motifs as well as new motifs, thereby serving to both validate the approach and project its usefulness in the finding and design of novel compounds.