Identification of potential glutaminyl cyclase inhibitors from lead-like libraries by in silico and in vitro fragment-based screening
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- 作者：Mária Szaszkó ; István Hajdú ; Beáta Flachner ; Krisztina Dobi…
- 关键词：Fragment ; based screening ; Differential scanning fluorimetry ; Glutaminyl cyclase ; Fragment linking
- 刊名：Molecular Diversity
- 出版年：2017
- 出版时间：February 2017
- 年：2017
- 卷：21
- 期：1
- 页码：175-186
- 全文大小：
- 刊物类别：Chemistry and Materials Science
- 刊物主题：Biochemistry, general; Organic Chemistry; Polymer Sciences; Pharmacy;
- 出版者：Springer International Publishing
- ISSN：1573-501X
- 卷排序：21
文摘
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.