Exploring the Influence of the Protein Environment on Metal-Binding Pharmacophores

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• 作者：David P. Martin ; Patrick G. Blachly ; J. Andrew McCammon ; Seth M. Cohen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 28, 2014
• 年：2014
• 卷：57
• 期：16
• 页码：7126-7135
• 全文大小：455K
• ISSN：1520-4804

文摘

The binding of a series of metal-binding pharmacophores (MBPs) related to the ligand 1-hydroxypyridine-2-(1H)-thione (1,2-HOPTO) in the active site of human carbonic anhydrase II (hCAII) has been investigated. The presence and/or position of a single methyl substituent drastically alters inhibitor potency and can result in coordination modes not observed in small-molecule model complexes. It is shown that this unexpected binding mode is the result of a steric clash between the methyl group and a highly ordered water network in the active site that is further stabilized by the formation of a hydrogen bond and favorable hydrophobic contacts. The affinity of MBPs is dependent on a large number of factors including donor atom identity, orientation, electrostatics, and van der Waals interactions. These results suggest that metal coordination by metalloenzyme inhibitors is a malleable interaction and that it is thus more appropriate to consider the metal-binding motif of these inhibitors as a pharmacophore rather than a 鈥渃helator鈥? The rational design of inhibitors targeting metalloenzymes will benefit greatly from a deeper understanding of the interplay between the variety of forces governing the binding of MBPs to active site metal ions.