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

A glutaminyl cyclase(QC) fragmentlibrary was in silico selected by disconnection of the structure of known QC inhibitors and by lead-like 2D virtual screeningof the same set. The resulting fragmentlibrary (204 compounds) was acquired from commercial suppliers and pre-screened by differential scanning fluorimetry followed by functional in vitro assays. In this way, 10 fragmenthits 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 fragmentsbound to different regions in a complementary manner, and thus, linking those fragmentsoffered 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 PubChemsearch confirmed that the best scoring analogues are novel, potential QC inhibitors.