Computer-aided molecular design of some indolinone derivatives of PLK4 inhibitors as novel anti-proliferative agents

Among the most well-known members of the mitotic protein kinase family are polo-like kinases. Polo-like kinase 4 as a type of this family is used as a therapeutic target in the treatment of proliferative diseases. A three-dimensional quantitative structure activity relationship study with comparative molecular field analysis and comparative molecular similarity indices analysis was carried out on a data set of 47 molecules consisting of (E)-3-((1H-indazol-6-yl)methylene) indolin-2-ones derivatives of polo-like kinase 4 inhibitors to rational design of new drug. The validity of model was tested with a data set divided into training and test set. All constructed models show good statistical reliability in terms of predicting polo-like kinase inhibitory activity of the molecules, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. Moreover, molecular docking with CDOCKER algorithm was done to investigate interactions of between ligand and protein and to achieve bioactive ligand conformer. The energy difference between the highest occupied molecular orbital and the lowest unoccupied molecular orbital (gap) implicitly stated the high reactivity of the most active molecule in the active site of protein. Furthermore, the molecular electrostatic potential energy at density functional theorylevel confirm the results from molecular docking. The identified key features obtained from the quantitative structure activity relationship modeling enabled us to design novel indolinone derivatives. In silico absorption, distribution, metabolism and excretion and toxicity risk assessment analyses were carried out on the new molecules to investigate compliance with the standard ranges.