Abstract
As the considerable technical challenges involved with generating crystal structures of G (guanine nucleotide- binding) protein-coupled receptors (GPCRs) are starting to be successfully addressed, opportunities to apply fragment-based drug discovery (FBDD) to this class of target are becoming a reality. GPCRs represent a large and important family of drug targets with considerable clinical and commercial interest. While their general seven transmembrane helix bundle structures are amenable to therapeutic intervention with small molecules, to date successful drugs have primarily been discovered using traditional competitive or function-based screening. With advances in biophysical screening techniques such as Surface Plasmon Resonance (SPR) and Target-Immobilised NMR Screening (TINS), being matched to developments in molecular dynamics simulations, virtual screening and stabilisation of biologically relevant conformations of GPCRs, structure-based approaches using fragment starting points are beginning to be applied to the discovery of new generations of small molecules.
Keywords: FBDD, Fragment-based drug discovery, Fragments, GPCR, G Protein-coupled receptors, Small molecules.
Current Topics in Medicinal Chemistry
Title:G Protein-Coupled Receptors - Targets for Fragment-based Drug Discovery
Volume: 15 Issue: 24
Author(s): Alastair D.G. Lawson
Affiliation:
Keywords: FBDD, Fragment-based drug discovery, Fragments, GPCR, G Protein-coupled receptors, Small molecules.
Abstract: As the considerable technical challenges involved with generating crystal structures of G (guanine nucleotide- binding) protein-coupled receptors (GPCRs) are starting to be successfully addressed, opportunities to apply fragment-based drug discovery (FBDD) to this class of target are becoming a reality. GPCRs represent a large and important family of drug targets with considerable clinical and commercial interest. While their general seven transmembrane helix bundle structures are amenable to therapeutic intervention with small molecules, to date successful drugs have primarily been discovered using traditional competitive or function-based screening. With advances in biophysical screening techniques such as Surface Plasmon Resonance (SPR) and Target-Immobilised NMR Screening (TINS), being matched to developments in molecular dynamics simulations, virtual screening and stabilisation of biologically relevant conformations of GPCRs, structure-based approaches using fragment starting points are beginning to be applied to the discovery of new generations of small molecules.
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Cite this article as:
Lawson D.G. Alastair, G Protein-Coupled Receptors - Targets for Fragment-based Drug Discovery, Current Topics in Medicinal Chemistry 2015; 15 (24) . https://dx.doi.org/10.2174/1568026615666150701113151
DOI https://dx.doi.org/10.2174/1568026615666150701113151 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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