Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119991, Russia.
Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 119991, Russia.
Biochemistry (Mosc). 2022 May;87(5):443-449. doi: 10.1134/S0006297922050054.
tRNA-guanine transglycosylase, an enzyme catalyzing replacement of guanine with queuine in human tRNA and participating in the translation mechanism, is involved in the development of cancer. However, information on the small-molecule inhibitors that can suppress activity of this enzyme is very limited. Molecular dynamics simulations were used to determine the amino acid residues that provide efficient binding of inhibitors in the active site of tRNA-guanine transglycosylase. It was demonstrated using 7-methylguanine molecule as a probe that the ability of the inhibitor to adopt a charged state in the environment of hydrogen bond acceptors Asp105 and Asp159 plays a key role in complex formation. Formation of the hydrogen bonds and hydrophobic contacts with Gln202, Gly229, Phe109, and Met259 residues are also important. It has been predicted that introduction of the substituents would have a different effect on the ability to inhibit tRNA-guanine transglycosylase, as well as the DNA repair protein poly(ADP-ribose) polymerase 1, which can contribute to the development of more efficient and selective compounds.
tRNA 鸟嘌呤转糖基酶是一种酶，可催化人 tRNA 中鸟嘌呤被 queuine 取代，并参与翻译机制，与癌症的发展有关。然而，能够抑制该酶活性的小分子抑制剂的信息非常有限。分子动力学模拟用于确定在 tRNA 鸟嘌呤转糖基酶的活性部位提供抑制剂有效结合的氨基酸残基。使用 7-甲基鸟嘌呤分子作为探针证明，抑制剂在氢键受体 Asp105 和 Asp159 环境中采用带电状态的能力在复合物形成中起着关键作用。与 Gln202、Gly229、Phe109 和 Met259 残基形成氢键和疏水接触也很重要。据预测，取代基的引入将对抑制 tRNA 鸟嘌呤转糖基酶的能力以及 DNA 修复蛋白聚（ADP-核糖）聚合酶 1 产生不同的影响，这有助于开发更有效和选择性的化合物。
