亲电酮类HDAC抑制剂的3D-QSAR和分子对接研究

摘要

Histone deacetylases (HDACI) are important targets for cancer treatment. Multiple drags of hydroxyl acid and benzamide have entered clinical trials,but the research of electrophilic ketones was still limited. To study the relationship between the bioactivity and structure of electrophilic ketones HDACi,a 3D-QSAR( three dimensional Quantitative Structure Activity Relationship) model was established using comparative molecular field analysis ( CoMFA) and comparative similarity indices analysis ( CoMSIA) methods. The cross-validated coefficient ( q2) of CoMFA was 0.668, the non-cross-validated r2 was 0. 999, the cross-validated coefficient(q2)of CoMSIA was 0. 686, and the non-cross-validated r2 was 0.995. Results showed that the model established has a good predictive ability. Surflex-dock was used to dock histone deacetylase inhibitor into histone molecules. The interaction between ligands and the receptor revealed the binding mode of the inhibitors in the active site of HDAC, and it can be used to guide the drug-design and synthesis.%组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACi)是近年来治疗癌症的重要靶向药物,其中羟氨酸类,苯甲酰胺类多种药物已进入临床试验阶段,但对于亲电酮类HDACi还有待于进一步研究,本研究应用比较分子力场分析法(comparative molecular field analysis,CoMFA),比较分子相似性指数法(comparafive similarity indices analysis,CoMSIA)对29个亲电酮类HDAC抑制剂分子进行了定量构效关系分析,CoMFA模型的q2 =0.668,r2=0.999; CoMSIA模型的q2=0.686,r2=0.995,所建模型预测能力较好.分子对接(surflex-dock)研究也进一步揭示出抑制剂分子与蛋白酶的作用模式,结合其作用模式比较合理地探讨了这类抑制剂的活性原因,为设计新型高效的亲电酮类HDACi提供了理论依据.