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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 (\(\sim \)5 % hit rate, best inhibitory activity: 16 \(\upmu \hbox {M}\)). 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.

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Acknowledgements

This work was partially supported by OTKA grants NK100482 and K115698 (to C. M. and I. S.), by the Richter Thematic Research Grant (to M. S., Z. L, S. C., G. D) and by the Hungarian Government (National Research, Technology and Innovation Fund, KMR_12-1-2012-0218, to M. S., Z. L, S. C., G. D). We are grateful to ChemAxon Ltd., Budapest for providing Instant JChem software for 2D similarity search and physicochemical parameter prediction.

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Correspondence to György Dormán.

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Szaszkó, M., Hajdú, I., Flachner, B. et al. Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening. Mol Divers 21, 175–186 (2017). https://doi.org/10.1007/s11030-016-9717-4

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Keywords

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