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首页> 外文期刊>Future medicinal chemistry >Hologram quantitative structure-activity relationship and comparative molecular interaction field analysis of aminothiazole and thiazolesulfonamide as reversible LSD1 inhibitors
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Hologram quantitative structure-activity relationship and comparative molecular interaction field analysis of aminothiazole and thiazolesulfonamide as reversible LSD1 inhibitors

机译：氨基噻唑和噻唑磺酰胺作为可逆LSD1抑制剂的全息图定量构效关系和比较分子相互作用场分析

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Background: LSD-1 is an enzyme that removes methyl groups from lysine residues of histone proteins. LSD-1 inhibition decreases cellular proliferation and therefore represents a therapeutic target for cancer treatment. MAO and LSD-1 are both flavin adenine dinucleotide-dependent MAOs, and the MAO inhibitor, tranylcypromine, is currently undergoing clinical trials for cancer treatment because it acts as an irreversible LSD-1 inhibitor. Materials & methods: The present study investigated new reversible LSD-1 inhibitors, in order to develop novel selective anticancer agents. We constructed 2 and 3D quantitative structure-activity relationship models by using a series of 54 aminothiazole and thiazolesulfonamide derivatives. Results: The models were validated internally and externally (q(2), 0.691 and 0.701; r(2), 0.894 and 0.937; r(test)(2), 0.785 and 0.644, for 2 and 3D models, respectively). Fragment contribution maps, as well as steric and electrostatic contour maps were generated in order to obtain chemical information related to LSD-1 inhibition. Conclusion: The thiazolesulfonamide group was fundamental to the inhibition of LSD-1 by these compounds and that bulky and aromatic substituents at the thiazole ring were important for their steric and electrostatic interactions with the active site of LSD-1.
机译：背景：LSD-1是一种从组蛋白的赖氨酸残基上去除甲基的酶。 LSD-1抑制作用会降低细胞增殖，因此代表了癌症治疗的治疗目标。 MAO和LSD-1都是黄素腺嘌呤二核苷酸依赖性MAO，并且MAO抑制剂tranylcypromine目前正在临床试验中用于癌症治疗，因为它起不可逆的LSD-1抑制剂的作用。材料与方法：本研究调查了新型可逆LSD-1抑制剂，以开发新型选择性抗癌药。我们使用一系列54个氨基噻唑和噻唑磺酰胺衍生物构建了2D和3D定量构效关系模型。结果：对模型进行了内部和外部验证（对于2D和3D模型，q（2），0.691和0.701; r（2），0.894和0.937; r（test）（2），0.785和0.644）。生成片段贡献图以及空间和静电等高线图，以获得与LSD-1抑制有关的化学信息。结论：噻唑磺酰胺基团是这些化合物抑制LSD-1的基础，噻唑环上的庞大和芳香取代基对于它们与LSD-1活性位点的空间和静电相互作用至关重要。

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