The Underestimated Halogen Bonds Forming with Protein Side Chains in Drug Discovery and Design

doi:10.1021/acs.jcim.6b00628

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	The Underestimated Halogen Bonds Forming with Protein Side Chains in Drug Discovery and Design
	Zhang, Qian 1; Xu, Zhijian2 ; Zhu, Weiliang2
刊名	JOURNAL OF CHEMICAL INFORMATION AND MODELING
	2017-01
卷号	57 期号:1 页码:22-26
ISSN号	1549-9596
DOI	10.1021/acs.jcim.6b00628
文献子类	Article
英文摘要	Halogen bonds (XBs) have been attracting increasing attention in biological systems, especially in drug discovery and design, for their advantages of both improving drug-target binding affinity and tuning ADME/T properties. After a comprehensive literature survey in drug discovery and design, we found that most of the studies on XBs between ligands and proteins have focused on the protein backbone. Meanwhile, we also noticed that the proportion of side-chain XBs to overall XBs decreases as structural resolution becomes lower and lower. We postulated that protein side chains are more flexible in comparison with backbone structures, leading to more unclear electron density and lower resolution of the side chains. As the classic force field used to refine protein structures from diffraction data cannot handle XBs correctly, some of the interactions are lost during the refinement. On the contrary, there is no change in the corresponding ratio of hydrogen bonds (HBs) during structural resolution because HBs can be handled well with the classic force field. Further analysis revealed that Thr and Gln account for a large part of the decreasing XB trend, which could be partly attributed to the misidentified N, C, or O atoms. In addition, the lost XBs might be recovered after the atoms are reassigned, e.g., by flipping Thr side chains. In summary, formation of XBs with protein side chains is underestimated, and more attention should be paid to the potential formation of XBs between orgatiohalogens and protein side chains during X-ray crystallography studies.
资助项目	National Natural Science Foundation of China[41301472] ; National Natural Science Foundation of China[81302699] ; National Natural Science Foundation of China[81273435] ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development" Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020309]
WOS关键词	ENRICHED FRAGMENT LIBRARIES ; MEDICINAL CHEMISTRY ; INHIBITORS ; RECOGNITION ; BINDING ; TARGET ; PROBES
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000392687400004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275746]
专题	药物发现与设计中心
通讯作者	Xu, Zhijian; Zhu, Weiliang
作者单位	1.East China Normal Univ, Dept Comp Sci & Technol, Shanghai 200241, Peoples R China; 2.Chinese Acad Sci, CAS Key Lab Receptor Res, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Qian,Xu, Zhijian,Zhu, Weiliang. The Underestimated Halogen Bonds Forming with Protein Side Chains in Drug Discovery and Design[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2017,57(1):22-26.
APA	Zhang, Qian,Xu, Zhijian,&Zhu, Weiliang.(2017).The Underestimated Halogen Bonds Forming with Protein Side Chains in Drug Discovery and Design.JOURNAL OF CHEMICAL INFORMATION AND MODELING,57(1),22-26.
MLA	Zhang, Qian,et al."The Underestimated Halogen Bonds Forming with Protein Side Chains in Drug Discovery and Design".JOURNAL OF CHEMICAL INFORMATION AND MODELING 57.1(2017):22-26.