MOLECULAR MODELING IN CHEMICAL CARCINOGENESIS

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The structures of mutagens/carcinogens are important determinants of their ability to react efficiently with DNA to give DNA adducts, and the conformations of these adducts are likely to be important in their ability to induce effectively the mutations that lead to cancer. The structures of mutagens/carcinogens in DNA can be studied by molecular modeling techniques. Herein, the study of the interaction of a variety of mutagen/carcinogens with DNA is proposed, including; thymine glycol, ethenoadenine, O2alkylthymines, O4alkylthymines, methylchrysenes and aflatoxins. In all cases encouraging preliminary results have been obtained: a mechanism by which thymine glycol might induce Thy to Cyt mutations has been described; a sensible rationale for the more rapid incorporation of d(O2iPrThy)TP compared to d(O2MeThy)TP opposite Ade in DNA by DNA polymerase in vitro has been found; 5-methylchrysene has a crowded bay region, and this has implications for its interaction with DNA as revealed by molecular modeling; and, five binding sites between aflatoxin B1 and DNA have been described. Each of these projects will be extended.