Receptor-based virtual screening and biological characterization of new inhibitors of Human Apurinic/Apyrimidinic Endonuclease Enzyme (Ape1)

The endonucleolytic activity of human apurinic/apyrimidinic endonuclease (AP endo, Ape1) is a major factor in the maintenance of the integrity of the genome. On the other side, as an undesired effect, Ape1 overexpression has been linked to resistance to radioand chemo-therapy treatments in several human tumors. Inhibition of Ape1 using siRNA or the expression of a dominant-negative form of the protein have been shown to sensitize cells to DNA-damaging agents, including various chemotherapeutic agents. Therefore, inhibition of the enzymatic activity of Ape1 might result in a potent antitumor therapy. Small molecules have been described as Ape1 inhibitors; yet, those compounds are in an early stage of development. Here we report for the first time the identification of new compounds as potential Ape1 inhibitors by using docking-based virtual screening technique. Some of these identified compounds are shown to be active in vitro with activities in the low to the medium micromolar range. Interaction of these compounds with Ape1 protein was observed by mass spectrometry. These molecules also potentiate the cytotoxicity of the chemotherapeutic agent methylmethane sulfonate in fribrosarcoma cells. This study demonstrate the power of the docking and virtual screening techniques as a first step for potential drugs design and opens the door to the development of a new generation of