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New Hits as Antagonists of GPR103 Identified by HTS
journal contribution
posted on 2014-05-08, 00:00 authored by Anneli Nordqvist, Lisbeth Kristensson, Kjell E. Johansson, Krystle Isaksson da Silva, Tomas Fex, Christian Tyrchan, Anette Svensson Henriksson, Kristina NilssonPreclinical data indicate that GPR103
receptor and its endogenous
neuropeptides QRFP26 and QRFP43 are involved in appetite regulation.
A high throughput screening (HTS) for small molecule GPR103 antagonists
was performed with the clinical goal to target weight management by
modulation of appetite. A high hit rate from the HTS and initial low
confirmation with respect to functional versus affinity data challenged
us to revise the established screening cascade. To secure high quality
data while increasing throughput, the binding assay was optimized
on quality to run at single concentration. This strategy enabled evaluation
of a larger fraction of chemical clusters and singletons delivering
17 new compound classes for GPR103 antagonism. Representative compounds
from three clusters are presented. One of the identified clusters
was further investigated, and an initial structure–activity
relationship study is reported. The most potent compound identified
had a pIC50 of 7.9 with an improved ligand lipophilic efficiency.
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affinity dataligand lipophilic efficiencyquality datacompound classesthroughput screeningGPR 103 receptorchemical clustersQRFP 43screening cascaderepresentative compoundsbinding assayneuropeptides QRFP 26molecule GPR 103 antagonistsNew HitsGPR 103 IdentifiedpIC 50target weight managementGPR 103 antagonismHTSPreclinical dataappetite regulation
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