近日，中科院上海药物所药物发现与设计中心（DDDC）朱维良课题组在最近一期的美国《药物化学杂志》(Journal of Medicinal Chemistry，2009，52，2854-2862)上发表论文，首次阐明了生物大分子中卤键的特征及其在药物设计中的潜在应用。

近年来，卤键在晶体工程、超分子组装和分子识别等众多领域得到了人们的广泛关注，基于卤键设计的液晶材料已经应用于工业生产中，但国内外关于生物体系中卤键的研究报导几乎为空白。因此，系统地研究生物体系中的卤键，特别是蛋白质与卤代配体间可能的卤键，阐明卤键在配体识别过程中的作用，对药物发现与设计有重要意义。

朱维良课题组博士后卢运祥等详细统计了蛋白质结构数据库 （PDB）中的卤键作用情况，采用QM/MM方法研究了一些代表性的蛋白质-配体复合物中的卤键性质。结果表明，卤键普遍存在于蛋白质-配体复合物中，强度与传统氢键相当，这种作用对活性位点小分子抑制剂的结合构象起到重要作用，但生物体系中的卤键明显偏离了无机体系中的直线作用形式。文章的审稿人均对论文给予了高度评价。文章发表后，已经引起了国内外有关研究机构的浓厚兴趣。

推荐原始出处：

J. Med. Chem., 2009, 52 (9), pp 2854–2862 DOI: 10.1021/jm9000133

Halogen BondingA Novel Interaction for Rational Drug Design?

Yunxiang Lu*?, Ting Shi?, Yong Wang?, Huaiyu Yang?, Xiuhua Yan?, Xiaoming Luo?, Hualiang Jiang? and Weiliang Zhu*??

Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, and School of Science, East China University of Science and Technology, Shanghai, 200237, China

Although recognized in small molecules for quite some time, the implications of halogen bonding in biomolecular systems are only now coming to light. In this study, several systems of proteins in complex with halogenated ligands have been investigated by using a two-layer QM/MM ONIOM methodology. In all cases, the halogen?oxygen distances are shown to be much less than the van der Waals radius sums. Single-point energy calculations unveil that the interaction becomes comparable in magnitude to classical hydrogen bonding. Furthermore, we found that the strength of the interactions attenuates in the order H ≈ I > Br > Cl. These results agree well with the characteristics discovered within small model halogen-bonded systems. A detailed analysis of the interactions reveals that halogen bonding interactions are responsible for the different conformation of the molecules in the active site. This study would help to establish such interaction as a potential and effective tool in the context of drug design.