Structure-Based Consensus Scoring Scheme for Selecting Class A Aminergic GPCR Fragments

Ádám A. Kelemen, Róbert Kiss, György G. Ferenczy, László Kovács, Beáta Flachner, Zsolt Lorincz, György M. Keseru

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Aminergic G-protein coupled receptors (GPRCs) represent well-known targets of central nervous-system related diseases. In this study a structure-based consensus virtual screening scheme was developed for designing targeted fragment libraries against class A aminergic GPCRs. Nine representative aminergic GPCR structures were selected by first clustering available X-ray structures and then choosing the one in each cluster that performs best in self-docking calculations. A consensus scoring protocol was developed using known promiscuous aminergic ligands and decoys as a training set. The consensus score (FrACS - fragment aminergic consensus score) calculated for the optimized protein ensemble showed improved enrichments in most cases as compared to stand-alone structures. Retrospective validation was carried out on public screening data for aminergic targets (5-HT1 serotonin receptor, TA1 trace-amine receptor) showing 8-17-fold enrichments using an ensemble of aminergic receptor structures. The performance of the structure based FrACS in combination with our ligand-based prefilter (FrAGS) was investigated both in a retrospective validation on the ChEMBL database and in a prospective validation on an in-house fragment library. In prospective validation virtual fragment hits were tested on 5-HT6 serotonin receptors not involved in the development of FrACS. Six out of the 36 experimentally tested fragments exhibited remarkable antagonist efficacies, and 4 showed IC50 values in the low micromolar or submicromolar range in a cell-based assay. Both retrospective and prospective validations revealed that the methodology is suitable for designing focused class A GPCR fragment libraries from large screening decks, commercial compound collections, or virtual databases.

Original languageEnglish
Pages (from-to)412-422
Number of pages11
JournalJournal of Chemical Information and Modeling
Volume56
Issue number2
DOIs
Publication statusPublished - Feb 22 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

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