论文部分内容阅读
组蛋白乙酰化转移酶p300在肿瘤细胞的分化和增殖中起重要的作用。本文采用了基于蛋白结构多层次的虚拟筛选方法来寻找组蛋白乙酰化转移酶p300的全新先导化合物,从含有十万个类药化合物的筛选库中,筛选出33个打分较好的化合物进行活性测试,其中1个化合物4-乙酰基-2-甲基-N-吗啉-3,4-二氢-2H-苯并[b][1,4]噻嗪-7-磺酰胺(17)的生物活性达到微摩尔水平。基于预测的该化合物与p300结合的模型,对该化合物进行了初步的结构修饰,通过构效关系研究所获得的结果与计算模拟预测的结合模式一致。所发现的全新结构的p300抑制剂将有助于发展更有效和更具选择性的组蛋白乙酰转移酶抑制剂。
Histone acetylation transferase p300 plays an important role in the differentiation and proliferation of tumor cells. In this paper, a novel virtual screening method based on multi-level protein structure was used to search for a new leader compound of histone acetylation transferase p300. From the screening library containing one hundred thousands of drug-like compounds, 33 scored compounds were screened for activity One of the compounds, 4-acetyl-2-methyl-N-morpholine-3,4-dihydro-2H- benzo [b] [1, 4] thiazine-7-sulfonamide (17) Biological activity reached micromolar levels. Based on the predicted model of this compound binding to p300, a preliminary structural modification of this compound was performed. The results obtained by the structure-activity relationship study are consistent with those predicted by the computational simulation. The newly discovered p300 inhibitors will help to develop more effective and selective histone acetyltransferase inhibitors.