Docking Analysis and Multidimensional Hybrid QSAR Model of 1,4-Benzodiazepine-2,5-Diones as HDM2 Antagonists

作者：Dai, Yujie^*; Chen, Nan; Wang, Qiang; Zheng, Heng; Zhang, Xiuli; Jia, Shiru; Dong, Lilong; Feng, Dacheng

来源：Iranian Journal of Pharmaceutical Research, 2012, 11(3): 807-830.

• p53-HDM2 interaction
• Docking
• QSAR
• 1,4-benzodiazepine-2,5-diones
• CDOCKER

The inhibitors of p53-HDM2 interaction are attractive molecules for the treatment of wildtype p53 tumors. In order to search more potent HDM2 inhibitors, docking operation with CDOCKER protocol in Discovery Studio 2.1 (DS2.1) and multidimensional hybrid quantitative structure-activity relationship (QSAR) studies through the physiochemical properties obtained from DS2.1 and E-Dragon 1.0 as descriptors, have been performed on 59 1,4-benzodiazepine-2,5-diones which have p53-HDM2 interaction inhibitory activities. The docking results indicate that pi-pi interaction between the imidazole group in HIS96 and the aryl ring at 4-N of 1,4-benzodiazepine-2,5-dione may be one of the key factors for the combination of ligands with HDM2. Two QSAR models were obtained using genetic function approximation (GFA) and genetic partial least squares (G/PLS) based on the descriptors obtained from DS2.1 and E-dragon 1.0, respectively. The best model can explain 85.5% of the variance (R-adj(2)) while it could predict 81.7% of the variance (R-cv(2)). With this model, the bioactivities of some new compounds were predicted.

• 出版日期2012-8
• 单位河北医科大学; 山东大学; 中国药科大学; 天津科技大学