Structure-based studies on species-specific inhibition of thymidylate synthase
Structure-based studies on species-specific inhibition of thymidylate synthase
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DOI：
10.1016/s0925-4439(02)00083-2
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发表时间：
2002-07-18
影响因子：
6.2
通讯作者：
Stroud, RM
中科院分区：
文献类型：
--
作者：
Costi, MP;Tondi, D;Stroud, RM
胸苷酸合成酶（Thymidylate synthase， TS）是公认的抗癌化疗靶点。由于它在胸苷酸合成和DNA合成的唯一从头途径中发挥关键作用，因此它是所有生命形式中必不可少的酶。因此，它最近被认为是一种有价值的对抗传染病的新靶点。在这种情况下，物种特异性对于区分入侵微生物和人类宿主至关重要，而胸苷酸合成酶是最高度保守的酶之一。我们将基于结构的药物设计与快速合成技术和诱变技术结合起来，以迭代的方式开发新的抗叶酸药物，这些药物不是从底物和辅因子中衍生的，并了解观察到的物种特异性的分子基础。本文讨论了结构和计算研究在发现细菌TS、萘氨酸和丹酚衍生物的非类似抗叶酸抑制剂以及对其生物活性谱的理解中的作用。(C) 2002 Elsevier Science b.v.版权所有
Thymidylate synthase (TS) is a well-recognized target for anticancer chemotherapy. Due to its key role in the sole de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is an essential enzyme in all life forms. As such, it has been recently recognized as a valuable new target against infectious diseases. There is also a pressing need for new antimicrobial agents that are able to target strains that are drug resistant toward currently used drugs, In this context, species specificity is of crucial importance to distinguish between the invading microorganism and the human host, yet thymidylate synthase is among the most highly conserved enzymes. We combine structure-based drug design with rapid synthetic techniques and mutagenesis, in an iterative fashion, to develop novel antifolates that are not derived from the substrate and cofactor, and to understand the molecular basis for the observed species specificity. The role of structural and computational studies in the discovery of nomanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed. (C) 2002 Elsevier Science B.V All rights reserved.