O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr...O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr） in proteins. Dysregulations of cellular O-GlcNAc have been implicated in diabetes, neurodegenerative disease, and cancer, which brings great interest in developing potent and specific small-molecular OGT inhibitors. In this work, we performed virtual screening on OGT catalytic site to identify potential inhibitors. 7134792 drug-like compounds from ZINC （a free database of commercially available compounds for virtual screening） and 4287550 compounds generated by FOG （fragment optimized growth program） were screened and the top 116 compounds ranked by docking score were analyzed. By comparing the screening results, we found FOG program can generate more compounds with better docking scores than ZINC. The top ZINC compounds ranked by docking score were grouped into two classes, which held the binding positions of UDP and GlcNAc of UDP- GlcNAc. Combined with individual fragments in binding pocket, de novo compounds were designed and proved to have better docking score. The screened and designed compounds may become a starting point for developing new drugs.展开更多
文摘O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr） in proteins. Dysregulations of cellular O-GlcNAc have been implicated in diabetes, neurodegenerative disease, and cancer, which brings great interest in developing potent and specific small-molecular OGT inhibitors. In this work, we performed virtual screening on OGT catalytic site to identify potential inhibitors. 7134792 drug-like compounds from ZINC （a free database of commercially available compounds for virtual screening） and 4287550 compounds generated by FOG （fragment optimized growth program） were screened and the top 116 compounds ranked by docking score were analyzed. By comparing the screening results, we found FOG program can generate more compounds with better docking scores than ZINC. The top ZINC compounds ranked by docking score were grouped into two classes, which held the binding positions of UDP and GlcNAc of UDP- GlcNAc. Combined with individual fragments in binding pocket, de novo compounds were designed and proved to have better docking score. The screened and designed compounds may become a starting point for developing new drugs.
