Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening

Mária Szaszkó, István Hajdú, Beáta Flachner, Krisztina Dobi, Csaba Magyar, I. Simon, Zsolt Lőrincz, Zoltán Kapui, Tamás Pázmány, Sándor Cseh, György Dormán

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 (∼ 5 % hit rate, best inhibitory activity: 16 μ M). 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.

Original languageEnglish
Pages (from-to)175-186
Number of pages12
JournalMolecular Diversity
Volume21
Issue number1
DOIs
Publication statusPublished - Feb 1 2017

Keywords

  • Differential scanning fluorimetry
  • Fragment linking
  • Fragment-based screening
  • Glutaminyl cyclase

ASJC Scopus subject areas

  • Catalysis
  • Information Systems
  • Molecular Biology
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Szaszkó, M., Hajdú, I., Flachner, B., Dobi, K., Magyar, C., Simon, I., Lőrincz, Z., Kapui, Z., Pázmány, T., Cseh, S., & Dormán, G. (2017). Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening. Molecular Diversity, 21(1), 175-186. https://doi.org/10.1007/s11030-016-9717-4