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Balancing focused combinatorial libraries based on multiple GPCR ligands

  • GPCR Symposium
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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.

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Abbreviations

5HT1F :

5-Hydroxytryptamine (serotonin) receptor, subtype 1F

Boc:

tert-Butoxycarbonyl

CCR1:

Chemotactic cytokine receptor 1

GPCR:

G-protein coupled receptor

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Acknowledgements

The authors would like to thank Dick Cramer, Mike Lawless, Jon Swanson and Rob Jilek of Tripos, Inc., for their support and many helpful discussions about ChemSpace.

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Author notes

  1. Sun Choi

    Present address: College of Pharmacy and Division of Molecular Life Sciences, Ewha Womans University, Seoul, 120-750, South Korea

Authors and Affiliations

  1. Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, St Louis, MO, 63144, USA

    Farhad Soltanshahi, Tamsin E. Mansley, Sun Choi & Robert D. Clark

Authors
  1. Farhad Soltanshahi
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  2. Tamsin E. Mansley
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  3. Sun Choi
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  4. Robert D. Clark
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Corresponding author

Correspondence to Robert D. Clark.

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Soltanshahi, F., Mansley, T.E., Choi, S. et al. Balancing focused combinatorial libraries based on multiple GPCR ligands. J Comput Aided Mol Des 20, 529–538 (2006). https://doi.org/10.1007/s10822-006-9076-9

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  • DOI: https://doi.org/10.1007/s10822-006-9076-9

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