ABSTRACT
The inhibitors of p53-HDM2 interaction are attractive molecules for the treatment of wild-type 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 n-n interaction between the imidazole group in HIS96 and the aryl ring at 4-N of l, 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[2][cv] while it could predict 81.7% of the variance [R[2]CV] With this model, the bioactivities of some new compounds were predicted