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Balancing focused combinatorial libraries based on multiple GPCR ligands

Title
Balancing focused combinatorial libraries based on multiple GPCR ligands
Authors
Soltanshahi F.Mansley T.E.Choi S.Clark R.D.
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2006
Journal Title
Journal of Computer-Aided Molecular Design
ISSN
0920-654XJCR Link
Citation
vol. 20, no. 7-8, pp. 529 - 538
Indexed
SCI; SCIE; SCOPUS scopus
Abstract
G-Protein coupled receptors (GPCRs) are important targets for drug discovery, and combinatorial chemistry is an important tool for pharmaceutical development. The absence of detailed structural information, however, limits the kinds of combinatorial design techniques that can be applied to GPCR targets. This is particularly problematic given the current emphasis on focused combinatorial libraries. By linking an incremental construction method (OptDesign) to the very fast shape-matching capability of ChemSpace, we have created an efficient method for designing targeted sublibraries that are topomerically similar to known actives. Multi-objective scoring allows consideration of multiple queries (actives) simultaneously. This can lead to a distribution of products skewed towards one particular query structure, however, particularly when the ligands of interest are quite dissimilar to one another. A novel pivoting technique is described which makes it possible to generate promising designs even under those circumstances. The approach is illustrated by application to some serotonergic agonists and chemokine antagonists. © Springer Science+Business Media, LLC 2006.
DOI
10.1007/s10822-006-9076-9
Appears in Collections:
약학대학 > 약학과 > Journal papers
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