基于结构的组蛋白去乙酰化酶抑制剂虚拟筛选

Structure based virtual screening of HDAC inhibitors

组蛋白去乙酰化酶是抗肿瘤作用的新靶点,基于该酶复合物的三维结构,首先对具有分子多样性的数据库进行了虚拟筛选;然后根据已知HDAC抑制剂的结构特征和筛选的结果,以及与生物大分子互补性,选择合理的构建单元,组建靶向的虚拟组合库;最后进行数据库虚拟筛选,对分子对接的结果进行评分,选择出理论上与HDAC有较好结合能力的化合物,设计了酰胺类、脲类和酰肼类全新结构类型的HDAC抑制剂,初步生物活性评价结果表明,预期有生物活性的化合物显示出一定的HDAC酶抑制活性。

Histone deacetylase is a novel target for anticancer drugs. This paper is based on the crystal structure of a HDAC homolog complexed with Trichostatin A, virtual screening was used to analyze large diversity databases in order to identify possible new drug hits; on the ground of virtual screening results, the known inhibitors structures and the complementarity of enzyme, rational building blocks were selected to design a focused virtual combinatorial database. Then docking was performed and the high score compounds were selected. In this study three kinds of compounds were designed, which include acylamides, hydrazides and ureidos, with respect to find new structural lead compounds. The preliminary bioassay data indicate that some compounds with an anticipated good activity have HDAC inhibitions in some degree.