Kinase-likeness and kinase-privileged fragments: Toward virtual polypharmacology
Kinase-likeness and kinase-privileged fragments: Toward virtual polypharmacology
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DOI：
10.1021/jm701021b
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发表时间：
2008-03-13
影响因子：
7.3
通讯作者：
Murcko, Mark A.
中科院分区：
文献类型：
--
作者：
Aronov, Alex M.;McClain, Brian;Murcko, Mark A.
小分子蛋白激酶抑制剂被广泛用作生物试剂，并作为用于多种疾病的药物设计的先导。我们研究了类似激酶的现象，即，在激酶特异性亚结构片段的背景下，配体抑制蛋白激酶的倾向。分析了激酶抑制剂文库中多个结构片段相对于非激酶化合物的出现频率。称为“2-0”激酶相似性规则的结构片段计数的组合提供了激酶活性化合物的约5倍富集。这一规则已通过内部激酶反筛选数据进行了验证，并前瞻性地应用于发现上市药物中的激酶活性。此外，使用现有的结构数据询问了激酶识别中有区别的片段的作用，从而深入了解了它们对抑制剂效力和选择性的影响。这些片段之一，bisarylaniline，已被表征为具有特异性结合偏好的激酶特权片段，并与激酶内的活性增加有关。
Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. We investigated the phenomenon of kinase-likeness, i.e., the propensity of ligands to inhibit protein kinases, in the context of kinase-specific substructural fragments. The frequency of occurrence of multiple structural fragments in kinase inhibitor libraries relative to nonkinase compounds has been analyzed. A combination of structural fragment counts, termed the "2-0" kinase-likeness rule, provides approximately 5-fold enrichment in kinase active compounds. This rule has been validated using in-house kinase counterscreening data and applied prospectively to uncover kinase activities in marketed drugs. In addition, the role of discriminating fragments in kinase recognition was interrogated using available structural data, providing an insight into their effect on inhibitor potency and selectivity. One of these fragments, bisarylaniline, has been characterized as a kinase-privileged fragment with specific binding preferences and a link to increased activity within kinases.