Abstract

MDM2 is the key negative regulator of p53 and an important validated target for anticancer drug discovery. Using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches, we performed LibDock based 3D-QSAR study on 42 isoindolinone derived MDM2 inhibitors for the first time. We found in CoMFA model including steric and electrostatic fields for the training set, the cross-validated q² value was 0.66 and the non-cross-validated r² value was 0.98, while, the cross-validated q² value was 0.58 and the noncross- validated r² value was 0.96 in CoMSIA Model. These results indicated that the CoMFA and CoMSIA analyses are very useful tools in the development of more potent p53-MDM2 binding inhibitors.

Keywords: p53-MDM2, Isoindolinone, 3D-QSAR, LibDock.