The vascular endothelial growth factor （VEGF） and its receptor tyrosine kinases VEGFR-2 or kinase insertdomain receptor （KDR） have emerged as attractive targets for the design of novel anticancer agents. In the present work, molecular docking method combined with three dimensional quantitative structure-activity relationships （comparative molecular field analysis （CoMFA） and comparative molecular similarity indice analysis （CoMSIA）） to analyze the possible interactions between KDR and those derivatives which acted as selective inhibitors. The CoMFA and CoMSIA models gave a cross-validated coefficient Q2 of 0.713 and 0.549, non-cross-validated R2 values of 0.974 and 0.878, and predicted R2 values of 0.966 and 0.823, respectively. The 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. The information obtained from 3D-QSAR and docking studies were very helpful to design novel selective inhibitors of KDR with desired activity and good chemical property.
利用分子力场分析法(comparative molecular field analysis,CoMFA)、比较分子相似性指数法(comparative molecular similarity indices analysis,CoMSIA)和分子对接方法对一系列喹唑啉类TNKS抑制剂进行三维定量构效关系研究。构建的CoMFA(q^(2)=0.578,r^(2)=0.998,r^(2)_(pred)=0.815)和CoMSIA(q^(2)=0.624,r^(2)=0.929,r^(2)_(pred)=0.747)模型具有良好的鲁棒性、预测能力和机制可解释能力。分子对接实验结果表明:Ser1221和Gly1185是影响这些抑制剂活性的主要氨基酸。研究对设计新型TNKS抑制剂具有参考意义。
Embryonic ectoderm development(EED)has become a novel target for cancer treatment.In this study,a series of EED inhibitors was subjected to a three-dimensional quantitative structure-activity relationship(3D-QSAR)and molecular docking.Accordingly,this is the first of such 3D-QSAR studies in a series of EED inhibitors displaying anti-cancer pharmacological profiles.The CoMFA(q^(2)=0.792,r^(2)=0.994,r^(2)pred=0.74)and CoMSIA(q^(2)=0.873,r2=0.994,r^(2)pred=0.81)models demonstrated good robustness and predictive ability.Moreover,molecular docking suggested that cation-π,π-π stacking and hydrogen bonding interactions were the main factors affecting the activity of these inhibitors.Five new small molecules were designed based on the CoMFA and CoMSIA contour maps.These molecules were then submitted to further ADME studies,in which the ADME properties of the five designed molecules were found to be within a reasonable range.In view of the corresponding findings,this study may provide theoretical guidance for the rational design of novel EED inhibitors.
