Virtual Screening and X‑ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase

Thymidylate
synthase X (ThyX) represents an attractive target for tuberculosis
drug discovery. Herein, we selected 16 compounds through a virtual
screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with a nonsubstrate
analog inhibitor. Given the active site similarities between Mycobacterium tuberculosis ThyX (Mtb-ThyX)
and Tm-ThyX, our crystal structure paves the way for a structure-based
design of novel antimycobacterial compounds. The 1H-imidazo­[4,5-d]­pyridazine was identified as
scaffold for the development of Mtb-ThyX inhibitors.

胸苷酸合酶X（Thymidylate synthase X，ThyX）是结核病药物研发的极具吸引力的靶点。本研究通过虚拟筛选方法筛选得到16种化合物，并解析了首个海栖热袍菌（Thermatoga maritima，Tm）ThyX与非底物类似物抑制剂复合物的X射线晶体结构。鉴于结核分枝杆菌（Mycobacterium tuberculosis，Mtb）ThyX（Mtb-ThyX）与Tm-ThyX的活性位点具有相似性，该晶体结构为基于结构设计新型抗分枝杆菌化合物奠定了基础。本研究还鉴定出1H-咪唑并[4,5-d]哒嗪可作为开发Mtb-ThyX抑制剂的母核骨架。