Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Chem Biol Drug Des. 2011 Aug;78(2):211-23. doi: 10.1111/j.1747-0285.2011.01136.x. Epub 2011 Jun 16.
It has been estimated that nearly one-third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases, or many others in which the metal ion is either of catalytic or of structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high-throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal-binding pharmacophores in the current screening libraries. Herein, we describe a novel fragment-based drug discovery approach using a metal-targeting fragment library that is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target's metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein-targeted therapeutics.
据估计，近三分之一的功能蛋白含有金属离子。这些蛋白构成了广泛的可能的药物靶点，包括金属蛋白酶、脱氢酶、氧化还原酶、水解酶、脱乙酰酶或许多其他类型的酶，其中金属离子要么具有催化性质，要么具有结构性质。尽管金属离子在如此多类药物靶点中都起着重要作用，但目前的高通量筛选技术通常不会对这些蛋白质产生可行的命中，这可能是由于当前筛选库中缺乏适当的金属结合药效团。在此，我们描述了一种使用基于各种不同类型金属结合基团的金属靶向片段文库的新型基于片段的药物发现方法，这些基团旨在将片段可靠地锚定在靶标金属离子上。我们表明，该方法可以有效地鉴定出新型、有效和选择性的化合物，这些化合物可以很容易地开发成针对金属蛋白的治疗药物。
