文献类型：期刊文献

英文题名：Halogen Bond: Its Role beyond Drug-Target Binding Affinity for Drug Discovery and Development

作者：Xu, Zhijian[1];Yang, Zhuo[1];Liu, Yingtao[1];Lu, Yunxiang[2];Chen, Kaixian[1];Zhu, Weiliang[1]

机构：[1]Chinese Acad Sci, Drug Discovery & Design Ctr, Key Lab Receptor Res, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;[2]E China Univ Sci & Technol, Dept Chem, Shanghai 200237, Peoples R China

年份：2014

卷号：54

期号：1

起止页码：69

外文期刊名：JOURNAL OF CHEMICAL INFORMATION AND MODELING

收录：;EI(收录号：20140617279956);WOS:【SCI-EXPANDED(收录号:WOS:000330542800008)】；

基金：This research was supported by the Ministry of Science and Technology (2012AA01A305), the National Natural Science Foundation (81273435, 81302699, and 21103047), the Postdoctoral Science Foundation of China (2013M541568), the State Key Laboratory of Drug Research (SIMM1203KF-01), and the State Key Laboratory of Medicinal Chemical Biology, Nankai University (20130265).

语种：英文

外文关键词：Halogenation - Binding energy - Quantum chemistry - Surveys - Proteins

摘要：Halogen bond has attracted a great deal of attention in the past years for hit-to-lead-to-candidate optimization aiming at improving drug-target binding affinity. In general, heavy organohalogens (i.e., organochlorines, organobromines, and organoiodines) are capable of forming halogen bonds while organofluorines are not. In order to explore the possible roles that halogen bonds could play beyond improving binding affinity, we performed a detailed database survey and quantum chemistry calculation with close attention paid to (1) the change of the ratio of heavy organohalogens to organofluorines along the drug discovery and development process and (2) the halogen bonds between organohalogens and nonbiopolymers or nontarget biopolymers. Our database survey revealed that (1) an obviously increasing trend of the ratio of heavy organohalogens to organofluorines was observed along the drug discovery and development process, illustrating that more organofluorines are worn and eliminated than heavy organohalogens during the process, suggesting that heavy halogens with the capability of forming halogen bonds should have priority for lead optimization; and (2) more than 16% of the halogen bonds in PDB are formed between organohalogens and water, and nearly 20% of the halogen bonds are formed with the proteins that are involved in the ADME/T process. Our QM/MM calculations validated the contribution of the halogen bond to the binding between organohalogens and plasma transport proteins. Thus, halogen bonds could play roles not only in improving drug-target binding affinity but also in tuning ADME/T property. Therefore, we suggest that albeit halogenation is a valuable approach for improving ligand bioactivity, more attention should be paid in the future to the application of the halogen bond for ligand ADME/T property optimization.