同源模建和分子对接研究HDAC1/HDAC8的选择性

组蛋白去乙酰化酶(HDACs)是近年来治疗肿瘤的重要靶标之一.由于HDACs包含多种亚型,且各亚型的生理功能存在一定的差异,其选择性抑制剂的开发已成为当前的研发热点.我们通过同源模建的HDAC1结构,与已有的HDAC8晶体结构的活性位点进行比较分析,探讨了对两者选择性有重要影响的残基,为基于受体的选择性抑制剂研究提供重要信息.同时选择了52个HDAC抑制剂,分别建立了HDAC1、HDAC8的活性值与对接打分值的线性回归模型.所建的HDAC1和HDAC8的线性构效关系模型的非交叉验证系数R2分别为0.82和0.80,表明具有一定的统计学意义.利用所建模型对已设计合成的化合物进行了预测,预测结果对HDAC1、HDAC8选择性抑制剂的优化改造提供了一定的指导意义.

Homology Modeling and Molecular Docking Studies on the Selectivity of HDAC1/HDAC8

Histone deacetylases (HDACs) have emerged as important anti-tumor targets in recent years. As HDACs comprise multiple isoforms and there are different physiological functions among various isoforms, the development of selective HDAC inhibitors has attracted a great deal of attention. This study focused on the discovery of selective HDAC1, HDAC8 inhibitors and specifically a homology model for HDAC1 was generated. A comparison was made between the HDAC1 homology model and the crystal structure of HDAC8, which showed that some active site residues were different from each other and these residues played important roles in the selectivity between HDAC1 and HDAC8. Two linear regression models were established based on the inhibitory activities against HDAC1, HDAC8 and the docking scores of 52 compounds. The developed linear regression models for HDAC1 and HDAC8 have non-cross validated correlation coefficients R2 of 0.82 and 0.80, respectively, which indicates that the results are statistically significant. These models were used to predict the activities of the synthesized compounds and these prediction results can provide further insights into the selectivity of HDAC1, HDAC8.