caa a22 4500 467938644 CHVBK 20180406153005.0 cr unu---uuuuu 170328e20060801xx s 000 0 eng 10.1007/s10822-006-9076-9 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9076-9 Balancing focused combinatorial libraries based on multiple GPCR ligands [Elektronische Daten] [Farhad Soltanshahi, Tamsin Mansley, Sun Choi, Robert Clark] 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 ChemSpace nationallicence Combinatorial library nationallicence Library design nationallicence Multi-objective scoring nationallicence OptDesign nationallicence Pareto ranking nationallicence 5HT1F : 5-Hydroxytryptamine (serotonin) receptor, subtype 1F nationallicence Boc : tert-Butoxycarbonyl nationallicence CCR1 : Chemotactic cytokine receptor 1 nationallicence GPCR : G-protein coupled receptor nationallicence Soltanshahi Farhad Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut Mansley Tamsin Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut Choi Sun Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut Clark Robert Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 529-538 0920-654X 20:7-8<529 2006 20 10822 https://doi.org/10.1007/s10822-006-9076-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9076-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Soltanshahi Farhad Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 700 1- Mansley Tamsin Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 700 1- Choi Sun Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 700 1- Clark Robert Informatics Research Center, Tripos, Inc., 1699 S. Hanley Road, 63144, St Louis, MO, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/7-8(2006-08-01), 529-538 0920-654X 20:7-8<529 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer