Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai, China.
Chem Biol Drug Des. 2021 Feb;97(2):221-230. doi: 10.1111/cbdd.13774. Epub 2020 Sep 16.
Mitochondrial serine hydroxymethyltransferase 2 (SHMT2) is an important drug target in the one-carbon metabolic pathway, since its activity is critical for purine and pyrimidine biosynthesis. Additionally, it plays a prominent role during metabolic reprogramming of cancer cells, and SHMT2 inhibitors have proven useful as anticancer drugs. Compared to drugs targeting one-carbon metabolic enzymes (mainly dihydrofolate reductase and thymidylate synthase) that have been used for clinical treatment of cancer, efficient SHMT2-specific inhibitors are lacking. Therefore, we established a direct system for virtual screening, protein expression, and identification of inhibitors targeting SHMT2. First, 27 compounds qualifying as potential SHMT2 inhibitors were selected for biological activity verification through virtual screening of the 210 thousand compounds registered in the Specs database. Second, these 27 hits were subjected to quick screening by an in vitro non-competitive kinetic assay of SHMT2 single-enzyme catalysis. This allowed us to identify three compounds featuring medium-strength and non-competitive inhibition of SHMT2: AM-807/42004511 (IC = 14.52 ± 4.1665 μM), AM-807/40675298 (IC = 12.74 ± 5.8991 μM), and AM-807/42004633 (IC = 9.43 ± 0.5646 μM). We describe a quick screening method for the identification of inhibitors targeting SHMT2, providing a basis for subsequent identification and screening of new inhibitors.
线粒体丝氨酸羟甲基转移酶 2（SHMT2）是一碳代谢途径中的一个重要药物靶点，因为其活性对嘌呤和嘧啶的生物合成至关重要。此外，它在癌细胞的代谢重编程中发挥着突出的作用，SHMT2 抑制剂已被证明是有用的抗癌药物。与用于癌症临床治疗的靶向一碳代谢酶（主要是二氢叶酸还原酶和胸苷酸合成酶）的药物相比，缺乏有效的 SHMT2 特异性抑制剂。因此，我们建立了一个直接的虚拟筛选、蛋白质表达和抑制剂鉴定系统，用于靶向 SHMT2。首先，通过对 Specs 数据库中注册的 21 万种化合物进行虚拟筛选，选择了 27 种有潜力的 SHMT2 抑制剂进行生物活性验证。其次，对这 27 个命中化合物进行了 SHMT2 单酶催化的体外非竞争性动力学快速筛选，从中鉴定出三种对 SHMT2 具有中等强度和非竞争性抑制作用的化合物：AM-807/42004511（IC50=14.52±4.1665 μM）、AM-807/40675298（IC50=12.74±5.8991 μM）和 AM-807/42004633（IC50=9.43±0.5646 μM）。我们描述了一种快速筛选方法，用于鉴定靶向 SHMT2 的抑制剂，为后续鉴定和筛选新的抑制剂提供了依据。
