Due to its crucial role in DNA synthesis, thymidylate synthase (TS) has been considered as a potential therapeutic target. Inhibition of the enzyme is a promising strategy for the treatment of some hyperproliferative diseases, including infections. As TS species‐specific inhibitors would be able to distinguish between the host and the pathogens, developing highly selective inhibitors is of great clinical importance. TS is among the most highly conserved enzymes over evolutionary history, making the design of its species‐selective inhibitor significantly challenging. The chemical interaction space, governed by a set of non‐selective TS inhibitors, has been explored for human TS and its homologous proteins in both Toxoplasma gondii and Escherichia coli using proteochemometrics modeling (PCM). Validity, robustness, and prediction power of the PCM model have been assessed applying a diverse set of internal/external validation approaches. Our PCM model has provided major structural information, which is indeed of great help to design new TS species‐specific inhibitors with the simultaneous inhibition ability toward both T. gondii and E. coli. To show applicability of the PCM model, new compounds have been designed based on structural information provided by the constructed model. Final results have been very promising with regard to selectivity ratios of the designed compounds for different TS isoforms, confirming the applicability of the PCM model.

中文翻译：

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胸苷酸合酶抑制作用的起源的化学化学建模

由于其在DNA合成中的关键作用，胸苷酸合酶（TS）被认为是潜在的治疗靶标。抑制酶是治疗某些过度增殖性疾病（包括感染）的一种有前途的策略。由于TS物种特异性抑制剂可以区分宿主和病原体，因此开发高度选择性的抑制剂具有重要的临床意义。TS是进化史上最高度保守的酶之一，因此其物种选择性抑制剂的设计极具挑战性。已探索了由一系列非选择性TS抑制剂控制的化学相互作用空间，来研究弓形虫和大肠杆菌中的人类TS及其同源蛋白。使用蛋白化学计量学建模（PCM）。PCM模型的有效性，鲁棒性和预测能力已使用多种内部/外部验证方法进行了评估。我们的PCM模型提供了主要的结构信息，对于设计同时具有对弓形虫和大肠杆菌同时具有抑制能力的新型TS物种特异性抑制剂的确提供了极大帮助。为了显示PCM模型的适用性，已基于所构建模型提供的结构信息设计了新化合物。关于所设计的化合物对不同TS同工型的选择性比率，最终结果是非常有希望的，这证实了PCM模型的适用性。