How to Replace the Residual Solvation Shell of Polar Active Site Residues to Achieve Nanomolar Inhibition of tRNA‐Guanine Transglycosylase
How to Replace the Residual Solvation Shell of Polar Active Site Residues to Achieve Nanomolar Inhibition of tRNA‐Guanine Transglycosylase
复制标题
如何替换极性活性位点残基的残留溶剂化壳以实现tRNA-鸟嘌呤转糖基酶的纳摩尔抑制
DOI：
10.1002/cmdc.200900343
复制
发表时间：
2009
期刊：
影响因子：
3.4
通讯作者：
G. Klebe
中科院分区：
文献类型：
--
作者：
T. Ritschel;Philipp Kohler;G. Neudert;A. Heine;F. Diederich;G. Klebe
在一项计算和结构研究中，我们研究了一系列 4 取代的 lin-苯鸟嘌呤，它们是 tRNA-鸟嘌呤转糖基酶 (TGT) 的有效抑制剂，而 TGT 是治疗志贺氏菌病的假定靶点。乍一看，不言而喻的是，在糖基化酶催化中心的两个相邻天冬氨酸残基的羧酸根基团之间放置带正电荷的配体官能团会导致配体结合增强。在配体结合之前水分子的伴随置换似乎导致了天冬氨酸的部分溶剂化。然而，本文提出的案例研究表明，这个前提过于肤浅。与不与残余水壳相冲突的未取代的母体配体相比，在这样的关键位置放置可能带正电的氨基，干扰残余水溶剂化壳，至多是成本中性的。将羟基定向在该位置的配体显示出甚至降低的结合。基于氨基官能团的成本中性放置，疏水侧链现在可以进一步连接以填充远离天冬氨酸的小疏水袋，其效力不断增加。任何用非极性支架跨越两个天冬氨酸之间关键位置的尝试都只会减少结合，即使残余溶剂化壳的水被成功排斥。这一令人惊讶的观察结果促进了对水分子在极性活性位点残基残留溶剂化中的作用的详细分析。通过比较数据库分析、计算活性位点图谱和一系列晶体结构分析，研究了它们在 TGT 结合袋中的几何形状和假定替代。此外，附着的疏水部分的构象偏好解释了它们对结合亲和力逐渐增加的贡献。
In a computational and structural study, we investigated a series of 4‐substituted lin‐benzoguanines that are potent inhibitors of tRNA‐guanine transglycosylase (TGT), a putative target for the treatment of shigellosis. At first glance, it appears self‐evident that the placement of a positively charged ligand functional group between the carboxylate groups of two adjacent aspartate residues in the glycosylase catalytic center leads to enhanced ligand binding. The concomitant displacement of water molecules that partially solvate the aspartates prior to ligand binding appears to result as a consequence of this. However, the case study presented herein shows that this premise is much too superficial. Placement of a likely positively charged amino group at such a pivotal position, interfering with the residual water solvation shell, is at best cost‐neutral compared with the unsubstituted parent ligand not conflicting with the residual water shell. A ligand that orients a hydroxy group in this position shows even decreased binding. Based on the cost‐neutral placement of the amino functionality, hydrophobic side chains can now be further attached to fill, with increasing potency, a small hydrophobic pocket remote to the aspartates. Any attempts to cross the pivotal position between both aspartates with nonpolar scaffolds reveals only decreased binding, even though the waters of the residual solvation shell are successfully repelled. This surprising observation fostered a detailed analysis of the role of water molecules involved in the residual solvation of polar active site residues. Their geometry and putative replacement in the binding pocket of TGT has been studied by a comparative database analysis, computational active site mapping, and a series of crystal structure analyses. Furthermore, conformational preferences of attached hydrophobic moieties explain their contribution to a gradual increase in binding affinity.
影响因子：
5.6
作者：
STEWART, DE;SARKAR, A;WAMPLER, JE
通讯作者：
WAMPLER, JE