Abstract
GPCR binding site-directed techniques are rapidly evolving into powerful tools for modern drug discovery. Many of these approaches bridge chemistry and biology, which are inseparable concepts in nature but are often treated as separate worlds in drug discovery and science in general. This review shows with several examples how focusing on the binding site(s) has a clear advantage when it comes to establishing sequence-correlated pharmacological profiles. By organizing and comparing sequence and structural data it is possible to “borrow” SAR from similar targets to increase the speed of lead-finding and, potentially, to produce ligands for previously intractable receptors. Sequence motifs correlated with ligands can be applied in the design of target-specific focused libraries that are both efficient and cost-effective and should provide increased hit-rates over diversity screening. Furthermore, in the optimization phase, the binding motif approach offers the possibility to identify quickly the most likely off-target candidates to be chosen for selectivity screening, as well as potentially characterizing those pockets which may best be exploited for improved selectivity.
Keywords: Chemogenomics, GPCR, 7TM, lead generation, selectivity, polypharmacology, privileged structures, compound library design, SAR, hit-rates, selectivity screening, chemogenomic techniques, chemogenomic annotation, phylogenetic analysis
Current Topics in Medicinal Chemistry
Title: A Ligands View of Target Similarity: Chemogenomic Binding Site- Directed Techniques for Drug Discovery
Volume: 11 Issue: 15
Author(s): Stephen L. Garland and David E. Gloriam
Affiliation:
Keywords: Chemogenomics, GPCR, 7TM, lead generation, selectivity, polypharmacology, privileged structures, compound library design, SAR, hit-rates, selectivity screening, chemogenomic techniques, chemogenomic annotation, phylogenetic analysis
Abstract: GPCR binding site-directed techniques are rapidly evolving into powerful tools for modern drug discovery. Many of these approaches bridge chemistry and biology, which are inseparable concepts in nature but are often treated as separate worlds in drug discovery and science in general. This review shows with several examples how focusing on the binding site(s) has a clear advantage when it comes to establishing sequence-correlated pharmacological profiles. By organizing and comparing sequence and structural data it is possible to “borrow” SAR from similar targets to increase the speed of lead-finding and, potentially, to produce ligands for previously intractable receptors. Sequence motifs correlated with ligands can be applied in the design of target-specific focused libraries that are both efficient and cost-effective and should provide increased hit-rates over diversity screening. Furthermore, in the optimization phase, the binding motif approach offers the possibility to identify quickly the most likely off-target candidates to be chosen for selectivity screening, as well as potentially characterizing those pockets which may best be exploited for improved selectivity.
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Cite this article as:
L. Garland Stephen and E. Gloriam David, A Ligands View of Target Similarity: Chemogenomic Binding Site- Directed Techniques for Drug Discovery, Current Topics in Medicinal Chemistry 2011; 11 (15) . https://dx.doi.org/10.2174/156802611796391276
DOI https://dx.doi.org/10.2174/156802611796391276 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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