摘要
目的以氧肟酸类基质金属蛋白酶9(MMP-9)抑制剂为数据集进行分子设计研究,为后续新型抗乳腺癌药物的改造与研发提供参考。方法以文献中氧肟酸类MMP-9抑制剂为数据集,运用CoMFA和Topomer-CoMFA技术构建3D-QSAR模型,结合Topomer Search技术进行虚拟筛选,综合参考三维等势图信息与分子活性预测值进行分子设计。结果CoMFA和Topomer-CoMFA模型的交叉验证系数分别为q2=0.697和q2=0.519,拟合验证系数分别为r2=0.994和r2=0.982,表明模型具有良好的稳定性和预测能力。三维等势图提示,分子侧链的静电场贡献度较立体场大,进一步结合Topomer Search虚拟筛选方法构建出2个新的高活性抑制剂化合物。结论基于氧肟酸类MMP-9抑制剂的定量构效关系分析和虚拟筛选可用于MMP-9抑制剂的分子设计研究,为MMP-9靶向新药研发提供参考。
Objective The molecular design based on the data set of Matrix metalloproteinase-9(MMP-9)inhibitors of hydroxamate derivatives was carried out to provide reference for the reconstruction and development of new anti-breast cancer drugs.Methods The 3 dimensional quantitative structure-activity relationship(3D-QSAR)model was established based on the data set of MMP-9 inhibitors of hydroxamate derivatives in the literature by using CoMFA and Topomer-CoMFA technology.Virtual screening was performed with Topomer Search technology.And the molecular design was based on the three-dimensional contour map information and the predicted values of molecular activity.Results The cross validation coefficients of CoMFA and Topomer CoMFA models were q2=0.697 and q2=0.519,respectively,and the coefficients of determination were r2=0.994 and r2=0.982,respectively,indicating good stability and predictability of the model.The three dimensional contour map indicated that the contribution of the electrostatic field of the molecular side chain was greater than that of the steric field.Two new inhibitor compounds with high activity were constructed with the virtual screening method of Topomer Search.Conclusion Quantitative structure-activity relationship analysis and virtual screening based on MMP-9 inhibitors of hydroxamate derivatives can be effectively used in the molecular design of MMP-9 inhibitors,and provide reference for the research and development of MMP-9 targeted new drugs.
作者
张茹玉
叶潘
李月潞
周迎
陈秀奎
刘桦
Zhang Ruyu;Ye Pan;Li Yuelu;Zhou Ying;Chen Xiukui;Liu Hua(School of Clinical Medicine, Chengdu Medical College, Chengdu 610050, China;Biomedical Experimental Teaching Center, Chengdu Medical College, Chengdu 610050, China)
出处
《成都医学院学报》
CAS
2021年第5期571-576,共6页
Journal of Chengdu Medical College
基金
国家级大学生创新创业训练计划项目(No:201813705010)
四川养老与老年健康协同创新中心招标项目(No:YLZBZ1819)。
关键词
基质金属蛋白酶9抑制剂
三维定量构效关系
虚拟筛选
分子设计
Matrix metalloproteinase-9 inhibitors
3 dimensional quantitative structure-activity relationship(3D-QSAR)
Virtual screening
Molecular design
