摘要
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。
A growing body of evidence suggests that p300 histone acetyltransferase plays important roles in cancer cell differentiation and proliferation. Here, we employed structure-based hierarchical virtual screening method to identify novel lead compounds of p300 histone acetyltransferase. From a screening library containing approximate 100 000 diverse druglike compounds, 33 compounds were chosen for experimental testing and one compound, 4-acetyl-2-methyl-N-morpholino-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-sulfonamide （17）, showed as micromolar inhibitor. Based on its predicted binding pose, we investigated its binding characteristics by designing two series of structural modifications. The obtained structure-activity relationship results are consistent with the predicted binding model. We expect that the identified novel p300 histone acetyltransferase inhibitors will serve as starting points for further development of more potent and specific histone acetyltransferase inhibitors.
出处
《药学学报》
CAS
CSCD
北大核心
2013年第5期700-708,共9页
Acta Pharmaceutica Sinica
基金
Project supported by the Chinese Ministry of Science and Technology"973"Grant 2011CB812402(to NH)
