title: Structure-Based Consensus Scoring Scheme for Selecting Class A Aminergic GPCR Fragments.
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.
authors.forename: Ádám A
authors.initials: ÁA
authors.lastname: Kelemen
authors.forename: Róbert
authors.initials: R
authors.lastname: Kiss
authors.forename: György G
authors.initials: GG
authors.lastname: Ferenczy
authors.affiliation: Infarmatik, Inc. , 113 Barksdale Professional Center, Newark, Delaware 19711, United States.
authors.forename: László
authors.initials: L
authors.lastname: Kovács
authors.affiliation: TargetEx , Kft.; 4/a. Kápolna köz, Dunakeszi, 2120, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Flachner
authors.affiliation: TargetEx , Kft.; 4/a. Kápolna köz, Dunakeszi, 2120, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lőrincz
authors.forename: György M
authors.initials: GM
authors.lastname: Keserű
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*
chemical_list: D000588:Amines; D043562:Receptors, G-Protein-Coupled