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■ Inverted Positioning of DNMT1 Inhibitor in the Active Site of DNMT1 Caused by Hydrophobicity/Hydrophilicity of the Terminal Structure

Toshifumi Tojo,* Yuhei Kubo, Takeshi Kondo, and Makoto Yuasa

*Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan

Abstract

DNA (cytosine-5)-methyltransferase 1 (DNMT1) is one of the enzymes that regulate DNA modification. It has been demonstrated that overexpression of DNMT1 is associated with the development of cancer, making DNMT1 an attractive molecular target for cancer therapy. Focused on the terminal structures of existing DNMT1 inhibitors, we designed and screened test compounds that possessed another functional group. Binding simulations identified compounds with a trifluoromethylphenyl group to insert in an inverted position against DNMT1 compared to existing DNMT1 inhibitors. These results suggest that the binding form against DNMT1 may depend on the hydrophobicity/hydrophilicity of the inhibitor’s terminal structure.