Exploring the influence of the protein environment on metal-binding pharmacophores.
Exploring the influence of the protein environment on metal-binding pharmacophores.
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DOI：
10.1021/jm500984b
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发表时间：
2014-08-28
影响因子：
7.3
通讯作者：
Cohen SM
中科院分区：
文献类型：
--
作者：
Martin DP;Blachly PG;McCammon JA;Cohen SM
研究了一系列与配体1-羟基吡啶-2-（1H）-吡啶（1，2-HOPTO）相关的金属结合药效团（MBPs）在人碳酸酐酶II（hCAII）活性部位的结合。单个甲基取代基的存在和/或位置显著改变抑制剂效力，并且可导致在小分子模型复合物中未观察到的配位模式。结果表明，这种意想不到的结合模式是甲基和高度有序的水网络之间的空间冲突的结果在活性位点，进一步稳定的氢键和有利的疏水接触的形成。MBP的亲和力取决于大量因素，包括供体原子身份、取向、静电和货车范德华相互作用。这些结果表明，金属酶抑制剂的金属配位是一种可塑性的相互作用，因此，它是更合适的考虑这些抑制剂的金属结合基序作为药效团，而不是“螯合剂”。针对金属酶的抑制剂的合理设计将大大受益于更深层次的理解之间的相互作用的各种力之间的结合MBPs的活性位点金属离子。
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 “chelator”. 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.
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人类碳赤霉素II的活性位点中的短而强的氢键。
影响因子：
2.9
作者：
Avvaru, Balendu Sankara;Kim, Chae Un;Sippel, Katherine H.;Gruner, Sol M.;Agbandje-McKenna, Mavis;Silverman, David N.;McKenna, Robert
通讯作者：
McKenna, Robert
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4
作者：
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通讯作者：
Arnold, Eddy
影响因子：
2.4
作者：
ABRAMOVITCH, RA;KNAUS, EE
通讯作者：
KNAUS, EE
影响因子：
2.7
作者：
Innocenti, Alessio;Hilvo, Mika;Supuran, Claudiu T.
通讯作者：
Supuran, Claudiu T.