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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2008-2-7
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pubmed:abstractText |
Melanin-concentrating hormone receptor 1 (MCH-R1) is a G-protein-coupled receptor (GPCR) and a target for the development of therapeutics for obesity. The structure-based development of MCH-R1 and other GPCR antagonists is hampered by the lack of an available experimentally determined atomic structure. A ligand-steered homology modeling approach has been developed (where information about existing ligands is used explicitly to shape and optimize the binding site) followed by docking-based virtual screening. Top scoring compounds identified virtually were tested experimentally in an MCH-R1 competitive binding assay, and six novel chemotypes as low micromolar affinity antagonist "hits" were identified. This success rate is more than a 10-fold improvement over random high-throughput screening, which supports our ligand-steered method. Clearly, the ligand-steered homology modeling method reduces the uncertainty of structure modeling for difficult targets like GPCRs.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AbagyanRuben ARA,
pubmed-author:BayneMarvin LML,
pubmed-author:BurtonMarybeth SMS,
pubmed-author:CavasottoClaudio NCN,
pubmed-author:CzarnieckiMichael FMF,
pubmed-author:HawesBrian EBE,
pubmed-author:HineHeatherH,
pubmed-author:KocsiSue AnnSA,
pubmed-author:MonsmaFrederick JFJJr,
pubmed-author:MurgoloNicholas JNJ,
pubmed-author:O'NeillKim AKA,
pubmed-author:OrryAndrew J WAJ,
pubmed-author:VoigtJohannes HJH
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pubmed:issnType |
Print
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pubmed:day |
14
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
581-8
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pubmed:meshHeading |
pubmed-meshheading:18198821-Animals,
pubmed-meshheading:18198821-Binding, Competitive,
pubmed-meshheading:18198821-Binding Sites,
pubmed-meshheading:18198821-CHO Cells,
pubmed-meshheading:18198821-Cattle,
pubmed-meshheading:18198821-Cricetinae,
pubmed-meshheading:18198821-Cricetulus,
pubmed-meshheading:18198821-Databases, Factual,
pubmed-meshheading:18198821-Humans,
pubmed-meshheading:18198821-Ligands,
pubmed-meshheading:18198821-Models, Molecular,
pubmed-meshheading:18198821-Receptors, Pituitary Hormone,
pubmed-meshheading:18198821-Receptors, Somatostatin,
pubmed-meshheading:18198821-Rhodopsin,
pubmed-meshheading:18198821-Sequence Homology, Amino Acid,
pubmed-meshheading:18198821-Stochastic Processes,
pubmed-meshheading:18198821-Structure-Activity Relationship,
pubmed-meshheading:18198821-Thermodynamics
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pubmed:year |
2008
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pubmed:articleTitle |
Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening.
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pubmed:affiliation |
MolSoft LLC, La Jolla, CA 92037, USA. Claudio.N.Cavasotto@uth.tmc.edu
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pubmed:publicationType |
Journal Article
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