Puerta David T, Lewis Jana A, Cohen Seth M
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.
J Am Chem Soc. 2004 Jul 14;126(27):8388-9. doi: 10.1021/ja0485513.
In an effort to identify promising non-hydroxamate inhibitors of matrix metalloproteinases (MMPs), several new zinc-binding groups (ZBGs) based on pyrone, pyrothione, hydroxypyridinone, and hydroxypyridinethione chelators have been examined. Structural studies with tris(pyrazolyl)borate model complexes show that these ligands bind to the MMP active site zinc(II) ion in a bidentate fashion, similar to that found with hydroxamate-based inhibitors. Fluorescence- and colorimetric-based enzyme assays have been used to determine the IC50 values for these ZBGs against MMP-3; mixed O,S-donor ligands were found to be remarkably potent, with IC50 values as much as 700-fold lower than that found for acetohydroxamic acid. Inhibitory activity was found to parallel metal binding affinity as determined in titrations with model complexes. These results demonstrate that MPIs based on new ZBGs are feasible and may indeed improve the overall performance of inhibitors designed against these important medicinal targets.
为了鉴定有前景的基质金属蛋白酶（MMPs）非异羟肟酸抑制剂，已对几种基于吡喃酮、二硫代吡喃、羟基吡啶酮和羟基吡啶硫酮螯合剂的新型锌结合基团（ZBGs）进行了研究。用三（吡唑基）硼酸酯模型配合物进行的结构研究表明，这些配体以双齿方式与MMP活性位点的锌（II）离子结合，类似于基于异羟肟酸的抑制剂。基于荧光和比色法的酶分析已用于测定这些ZBGs对MMP-3的IC50值；发现混合的O，S供体配体具有显著的效力，其IC50值比乙酰氧肟酸低多达700倍。发现抑制活性与用模型配合物滴定测定的金属结合亲和力平行。这些结果表明，基于新型ZBGs的MPI是可行的，并且确实可能改善针对这些重要药物靶点设计的抑制剂的整体性能。
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