Chloroethylnitrosoureas (CENUs) are effective alkylating agents for the treatment of a variety of tumors including cerebroma, melanoma and lymphoma. However, further development and clinical application of CENUs were obstructed due to the drug resistance induced by O6-alkylguanine-DNA alkyltransferase (AGT). The AGT-mediated repair of DNA interstrand crosslinks (ICLs) was considered as the crucial process of the drug resistance to CENUs. In this work, the mechanism of DNA ICLs repair was investigated using molecular dynamics (AMBER), density functional theory (DFT-B3LYP) and QM/MM methods. The results indicated that the formation of AGT-DNA crosslink need to overcome a much lower energy barrier than that of ClEt-AGT, which suggested that the O6,N1-EtG intermediate should be the favorable substrate to be repaired by AGT. Moreover, the formation of AGT-DNA crosslink was competitive with the formation of DNA ICLs, which was the most important DNA damage for the cytotoxicity of CENUs.

Repair mechanism of DNA interstrand crosslinks by O<sup>6</sup>-alkylguanine transferase involved in the drug resistance to chloroethylnitrosoureas: A theoretical investigation

245th National Meeting (2013)

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Repair mechanism of DNA interstrand crosslinks by O6-alkylguanine transferase involved in the drug resistance to chloroethylnitrosoureas: A theoretical investigation

Repair mechanism of DNA interstrand crosslinks by O⁶-alkylguanine transferase involved in the drug resistance to chloroethylnitrosoureas: A theoretical investigation