Elucidating drug-metalloprotein interactions with tris(pyrazolyl)borate model complexes
Elucidating drug-metalloprotein interactions with tris(pyrazolyl)borate model complexes
复制标题
DOI：
10.1021/ic0204272
复制
发表时间：
2002-10-07
影响因子：
4.6
通讯作者：
Cohen, SM
中科院分区：
文献类型：
--
作者：
Puerta, DT;Cohen, SM
将四面体锌配合物[（Tp（Me，Ph））ZnOH]（Tp（Me，Ph）=氢化三（5，3-甲基苯基吡唑基）硼酸酯）与乙酰异羟肟酸、3-巯基-2-丁酮、N-（甲基）巯基乙酰胺、β-巯基乙醇、3-巯基-2-丙醇和3-巯基-2-丁醇结合以生成配合物[（Tp（Me，Ph））Zn（ZBG）]（ZBG =锌结合基团）。制备这些复合物以确定三种不同类型的硫醇衍生的基质金属蛋白酶（MMP）抑制剂的结合模式。所有六种金属配合物的固态结构通过X射线晶体学测定。结构表明，虽然β-巯基酮和β-巯基酰胺以双齿方式结合锌离子，但三种β-巯基醇化合物仅通过硫原子表现出单齿配位。在这项工作之前，没有实验数据可用于这些类型的抑制剂与MMP的锌活性位点的结合构象。这些模型研究的结果揭示了这些ZBG的不同结合模式，并有助于解释抑制试验的结果和第二代药物设计。这项工作证明了模型复合物作为揭示药物-金属蛋白相互作用的工具的实用性。
The tetrahedral zinc complex [(Tp(Me,Ph))ZnOH] (Tp(Me,Ph) = hydrotris(5,3-methylphenylpyrazolyl)borate) was combined with acetohydroxamic acid, 3-mercapto-2-butanone, N-(methyl)mercaptoacetamide, beta-mercaptoethanol, 3-mercapto2-propanol, and 3-mercapto-2-butanol to generate the complexes [(Tp(Me,Ph))Zn(ZBG)] (ZBG = zinc-binding group). These complexes were prepared to determine the mode of binding for three different types of thiol-derived matrix metalloproteinase (MMP) inhibitors. The solid-state structures of all six metal complexes were determined by X-ray crystallography. The structures reveal that while beta-mercaptoketones and beta-mercaptoamides bind the zinc ion in a bidentate fashion, the three beta-mercaptoalcohol compounds only demonstrate monodentate coordination via the sulfur atom. Prior to this work, no experimental data were available for the binding conformation of these types of inhibitors to the zinc active site of MMPs. The results of these model studies reveal different binding modes for these ZBGs and are useful for explaining the results of inhibition assays and in second-generation drug design. This work demonstrates the utility of model complexes as a tool for revealing drug-metalloprotein interactions.