Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria, and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, they have been underexplored to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors.

中文翻译：

---

使用基于片段的方法从结核分枝杆菌中鉴定靶向二氢叶酸还原酶的替代化学支架。

二氢叶酸还原酶（DHFR）是参与叶酸代谢的关键酶，在癌症，免疫疾病，细菌和原生动物感染的治疗中已被广泛研究。尽管已证明几种抗叶酸药可成功治疗传染病，但尽管结核分枝杆菌很重要，但它们仍未开发出抗击结核病的方法。DHFR（MtDHFR）。在本文中，我们描述了一种针对目标MtDHFR的基于片段的整合药物发现方法，该方法已经确定了使用该酶的任何先前药物设计活动中尚未探索的支架命中。通过内部库的目录策略对已鉴定片段之一应用SAR，导致一系列分子以低微摩尔亲和力与MtDHFR结合。MtDHFR的晶体结构与该系列化合物的复合物显示出一种新颖的结合模式，该模式与其他DHFR抗叶酸剂有很大不同，因此为开发相关MtDHFR抑制剂开辟了前景。