Full understanding of the enzyme O-GlcNAc transferase and all of its functional mechanisms and roles may represent the last piece in the jigsaw, which would confirm that errors in regulation of O-GlcNAcylation of proteins lead to numerous diseases, including type 2 diabetes, cancer and Alzheimer's disease. We used computer-aided drug design methodology to search for novel lead compounds, which would effectively inhibit OGT enzymatic activity. Our starting point was the OGT's natural substrate UDP-GlcNAc. Majority of the so far developed and tested inhibitors were active only in in vitro experiments and exhibited insufficient target specificity. In addition, most of them also suffer from a large degree of cell impermeability. Structure-based virtual screeening method of compound libraries offered us a new insight in the inhibitor design. Screening results of docking compounds into the UDP binding pocket of the OGT active site offered some really interesting results. Structure of 2-oxo-1,2-dihydroquinoline-4-carboxamide was a common structural feature of several compounds ranked amongst the best 25 hits. Researchers from the Chair of medicinal chemistry used it as a template structure for the synthesis of 22 new derivatives. In vitro testing results for these derivatives were very encouraging with some of the compounds (UL-AAS-4 and UL-AAS-5c) completely inhibiting the OGT activity at the tested concentration. Inhibition was also achieved with some other compounds ranked on the list of the best 25 hits. These laboratory tests results also confirmed the efficiency of the used methods for identifying new lead compounds. Most of the top ranked compounds have a molecular mass lower than 300 g/mol, which gives us a lot of space for future design and optimization of the selected compounds. With this work we merely made the first step in the long process of finding better inhibitors, though a very useful and important one.
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