State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
Toxicol Appl Pharmacol. 2019 May 1;370:106-116. doi: 10.1016/j.taap.2019.03.014. Epub 2019 Mar 18.
The selenoprotein thioredoxin reductase (TXNRD) is a promising therapeutic target for cancer. To discover novel TXNRD inhibitors, a library of α, β-unsaturated carbonyl compounds were applied in structure-based virtual screening for the selection of hit compounds. Fifteen top-ranked compounds were further validated experimentally, exhibiting potent inhibition of TXNRD and remarkable cytotoxicity to cancer cells. The further binding mode analysis indicated that multiple noncovalent interactions between the inhibitors and the active pocket of TXNRD facilitated the formation of covalent bonds between the Sec498 on TXNRD and the α, β-unsaturated carbonyl groups on inhibitors. Results from both simulations and experiments demonstrated that Sec498 is the prime interaction site for the inhibition of TXNRD. Taking compound 7 as an example, the inhibition of TXNRD by compounds promoted oxidative stress-mediated apoptosis of cancer cells. Given these findings, novel TXNRD inhibitors may be discovered and introduced to the growing fields of small molecule drugs against TXNRD.
硒蛋白硫氧还蛋白还原酶（TXNRD）是癌症治疗的一个很有前途的靶点。为了发现新型 TXNRD 抑制剂，应用了一个α，β-不饱和羰基化合物库进行基于结构的虚拟筛选，以选择命中化合物。对 15 个排名最高的化合物进行了进一步的实验验证，结果表明它们对 TXNRD 具有很强的抑制作用，并对癌细胞具有显著的细胞毒性。进一步的结合模式分析表明，抑制剂与 TXNRD 活性口袋之间的多种非共价相互作用促进了 TXNRD 上的 Sec498 与抑制剂上的α，β-不饱和羰基之间的形成共价键。模拟和实验结果都表明 Sec498 是抑制 TXNRD 的主要相互作用位点。以化合物 7 为例，化合物对 TXNRD 的抑制作用促进了氧化应激介导的癌细胞凋亡。鉴于这些发现，可能会发现新型 TXNRD 抑制剂，并将其引入针对 TXNRD 的小分子药物这一日益增长的领域。
