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Virtual Screening of Human O-GlcNAc Transferase Inhibitors
Qing-tong Zhou,Hao-jun Liang,Eugene Shakhnovich
Author NameAffiliationE-mail
Qing-tong Zhou Department of Polymer Science and Engineering, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei 230026, China;Department of Chemistry and Chemical Biology, Harvard University, Cambridge MA 02138, USA  
Hao-jun Liang Department of Polymer Science and Engineering, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Technology of China, Hefei 230026, China hjliang@ustc.edu.cn 
Eugene Shakhnovich Department of Chemistry and Chemical Biology, Harvard University, Cambridge MA 02138, USA shakhnovich@chemistry.harvard.edu 
Abstract:
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 speci c 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 UDPGlcNAc. 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.
Key words:  O-GlcNAc transferase  Virtual screening  Inhibitor  ZINC  FOG  Drug design
FundProject:This work is supported by the FAS Division of Science, Research Computing Group at Harvard University and the Supercomputing Center of USTC by the National Natural Science Foundation of China (No.20934004 and No.91127046), the National Institutes of Health (No.GM068670), and the China Scholarship Council.
基于结构的O-GlcNAc转移酶抑制剂的虚拟筛选
周庆同,梁好均,EugeneShakhnovich
摘要:
利用O-GlcNAc 转移酶同UDP-GlcNAc复合物的晶体结构,针对其催化位点,对ZINC库中的7134792个分子和FOG库中的4287550个分子进行三轮(HTVS、SP、XP)虚拟筛选,结果发现具有更好类药性的FOG库中包含更多对接得分更低的小分子,且具有更多新颖的化学片段.ZINC库中具有较低对接得分的分子可分为2类,分别占据UDP-GlcNAc的UDP和GlcNAc的结合位置,在此基础上设计得到的分子具有更好的对接得分.证明FOG分子库具有产生更多对接得分更低的分子,所预测和设计的小分子化合物可以成为潜在的抑制剂药物分子.
关键词:  O-GlcNAc 转移酶  ZINC  FOG  虚拟筛选  抑制剂  药物设计
DOI:10.1063/1674-0068/29/cjcp1510211
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