近日，中科院上海藥物所藥物發(fā)現(xiàn)與設(shè)計(jì)中心（DDDC）朱維良課題組在最近一期的美國《藥物化學(xué)雜志》(Journal of Medicinal Chemistry,，2009,，52，2854-2862)上發(fā)表論文,，首次闡明了生物大分子中鹵鍵的特征及其在藥物設(shè)計(jì)中的潛在應(yīng)用,。
近年來，鹵鍵在晶體工程,、超分子組裝和分子識(shí)別等眾多領(lǐng)域得到了人們的廣泛關(guān)注,，基于鹵鍵設(shè)計(jì)的液晶材料已經(jīng)應(yīng)用于工業(yè)生產(chǎn)中,，但國內(nèi)外關(guān)于生物體系中鹵鍵的研究報(bào)導(dǎo)幾乎為空白。因此,，系統(tǒng)地研究生物體系中的鹵鍵,，特別是蛋白質(zhì)與鹵代配體間可能的鹵鍵，闡明鹵鍵在配體識(shí)別過程中的作用,，對(duì)藥物發(fā)現(xiàn)與設(shè)計(jì)有重要意義,。
朱維良課題組博士后盧運(yùn)祥等詳細(xì)統(tǒng)計(jì)了蛋白質(zhì)結(jié)構(gòu)數(shù)據(jù)庫 （PDB）中的鹵鍵作用情況，采用QM/MM方法研究了一些代表性的蛋白質(zhì)-配體復(fù)合物中的鹵鍵性質(zhì),。結(jié)果表明,，鹵鍵普遍存在于蛋白質(zhì)-配體復(fù)合物中，強(qiáng)度與傳統(tǒng)氫鍵相當(dāng),，這種作用對(duì)活性位點(diǎn)小分子抑制劑的結(jié)合構(gòu)象起到重要作用，但生物體系中的鹵鍵明顯偏離了無機(jī)體系中的直線作用形式,。文章的審稿人均對(duì)論文給予了高度評(píng)價(jià),。文章發(fā)表后，已經(jīng)引起了國內(nèi)外有關(guān)研究機(jī)構(gòu)的濃厚興趣,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
