Abstract
GPCRs had significant representation in the drug discovery portfolios of most major commercial drug discovery organizations for many years. This is due in part to the diverse biological roles mediated by GPCRs as a class, as well as the empirical discovery that they have proven relatively tractable to the development of small molecule therapeutics. Publication of the human genome sequence in 2001 confirmed GPCRs as the largest single gene superfamily with more than 700 members, furthering the already strong appeal of addressing this target class using efficient and highly parallelized platform approaches. The GPCR research platform implemented at Amgen is used as a case study to review the evolution and implementation of available assays and technologies applicable to GPCR drug discovery. The strengths, weaknesses, and applications of assay technologies applicable to Gαs, Gαi and Gαq-coupled receptors are described and their relative merits evaluated. Particular consideration is made of the role and practice of “de-orphaning” and signaling pathway characterization as a pre-requisite to establishing effective screens. In silico and in vitro methodology developed for rapid, parallel high throughput hit characterization and prioritization is also discussed extensively.
Keywords: Orphan GPCR, GPCR, G protein-coupled receptor, assay development, high throughput screening, ligand hunting, agonist, antagonist, modulator, ligand
Combinatorial Chemistry & High Throughput Screening
Title: High Throughput Screening for Orphan and Liganded GPCRs
Volume: 11 Issue: 3
Author(s): Shou-Hua Xiao, Jeff D. Reagan, Paul H. Lee, Angela Fu, Ralf Schwandner, Xiaoning Zhao, Johannes Knop, Holger Beckmann and Stephen W. Young
Affiliation:
Keywords: Orphan GPCR, GPCR, G protein-coupled receptor, assay development, high throughput screening, ligand hunting, agonist, antagonist, modulator, ligand
Abstract: GPCRs had significant representation in the drug discovery portfolios of most major commercial drug discovery organizations for many years. This is due in part to the diverse biological roles mediated by GPCRs as a class, as well as the empirical discovery that they have proven relatively tractable to the development of small molecule therapeutics. Publication of the human genome sequence in 2001 confirmed GPCRs as the largest single gene superfamily with more than 700 members, furthering the already strong appeal of addressing this target class using efficient and highly parallelized platform approaches. The GPCR research platform implemented at Amgen is used as a case study to review the evolution and implementation of available assays and technologies applicable to GPCR drug discovery. The strengths, weaknesses, and applications of assay technologies applicable to Gαs, Gαi and Gαq-coupled receptors are described and their relative merits evaluated. Particular consideration is made of the role and practice of “de-orphaning” and signaling pathway characterization as a pre-requisite to establishing effective screens. In silico and in vitro methodology developed for rapid, parallel high throughput hit characterization and prioritization is also discussed extensively.
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Cite this article as:
Xiao Shou-Hua, Reagan D. Jeff, Lee H. Paul, Fu Angela, Schwandner Ralf, Zhao Xiaoning, Knop Johannes, Beckmann Holger and Young W. Stephen, High Throughput Screening for Orphan and Liganded GPCRs, Combinatorial Chemistry & High Throughput Screening 2008; 11 (3) . https://dx.doi.org/10.2174/138620708783877762
DOI https://dx.doi.org/10.2174/138620708783877762 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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