title: Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening.
abstract: A glutaminyl cyclase (QC) fragment library was in silico selected by disconnection of the structure of known QC inhibitors and by lead-like 2D virtual screening of the same set. The resulting fragment library (204 compounds) was acquired from commercial suppliers and pre-screened by differential scanning fluorimetry followed by functional in vitro assays. In this way, 10 fragment hits were identified ([Formula: see text]5 % hit rate, best inhibitory activity: 16 [Formula: see text]). The in vitro hits were then docked to the active site of QC, and the best scoring compounds were analyzed for binding interactions. Two fragments bound to different regions in a complementary manner, and thus, linking those fragments offered a rational strategy to generate novel QC inhibitors. Based on the structure of the virtual linked fragment, a 77-membered QC target focused library was selected from vendor databases and docked to the active site of QC. A PubChem search confirmed that the best scoring analogues are novel, potential QC inhibitors.
authors.affiliation: TargetEx Llc., Kápolna köz 4/a, Dunakeszi, 2120, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Szaszkó
authors.affiliation: TargetEx Llc., Kápolna köz 4/a, Dunakeszi, 2120, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Hajdú
authors.affiliation: TargetEx Llc., Kápolna köz 4/a, Dunakeszi, 2120, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Flachner
authors.affiliation: TargetEx Llc., Kápolna köz 4/a, Dunakeszi, 2120, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Dobi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Magyar
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest, 1117, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Simon
authors.affiliation: TargetEx Llc., Kápolna köz 4/a, Dunakeszi, 2120, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lőrincz
authors.affiliation: Gedeon Richter Plc., Gyömrői út 19-21, Budapest, 1103, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kapui
authors.affiliation: Gedeon Richter Plc., Gyömrői út 19-21, Budapest, 1103, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Pázmány
authors.affiliation: TargetEx Llc., Kápolna köz 4/a, Dunakeszi, 2120, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Cseh
authors.affiliation: TargetEx Llc., Kápolna köz 4/a, Dunakeszi, 2120, Hungary. dorman@targetex.com.
authors.forename: György
authors.identifier: http://orcid.org/0000-0001-7702-2206
authors.initials: G
authors.lastname: Dormán
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase
keywords: Differential scanning fluorimetry; Fragment linking; Fragment-based screening; Glutaminyl cyclase