Molecular Modeling in Chemical Carcinogenesis

Loechler, Edward L.

Abstract

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.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Research Project (R01)
• Project #: 1R01CA050432-01
• Application #: 3194892
• Study Section: Chemical Pathology Study Section (CPA)
• Project Start: 1989-12-01
• Project End: 1992-11-30
• Budget Start: 1989-12-01
• Budget End: 1990-11-30
• Support Year: 1
• Fiscal Year: 1990

Institution

• Name: Boston University
• Type: Schools of Arts and Sciences
• DUNS #: 604483045
• City: Boston
• State: MA
• Country: United States
• Zip Code: 02118

Publications

Kalam, M Abul; Haraguchi, Kazuhiro; Chandani, Sushil et al. (2006) Genetic effects of oxidative DNA damages: comparative mutagenesis of the imidazole ring-opened formamidopyrimidines (Fapy lesions) and 8-oxo-purines in simian kidney cells. Nucleic Acids Res 34:2305-15

Lee, Chiu Hong; Chandani, Sushil; Loechler, Edward L (2006) Homology modeling of four Y-family, lesion-bypass DNA polymerases: the case that E. coli Pol IV and human Pol kappa are orthologs, and E. coli Pol V and human Pol eta are orthologs. J Mol Graph Model 25:87-102

Chandani, Sushil; Lee, Chiu Hong; Loechler, Edward L (2005) Free-energy perturbation methods to study structure and energetics of DNA adducts: results for the major N2-dG adduct of benzo[a]pyrene in two conformations and different sequence contexts. Chem Res Toxicol 18:1108-23

Nagalingam, Arumugam; Seo, Kwang-Young; Loechler, Edward L (2005) Mutagenesis studies of the major benzo[a]pyrene N2-dG adduct in a 5'-TG versus a 5'-UG sequence: removal of the methyl group causes a modest decrease in the [G->T/G->A] mutational ratio. Mutagenesis 20:105-10

Yin, Jun; Seo, Kwang Young; Loechler, Edward L (2004) A role for DNA polymerase V in G --> T mutations from the major benzo[a]pyrene N2-dG adduct when studied in a 5'-TGT sequence in E. coli. DNA Repair (Amst) 3:323-34

Lee, Chiu Hong; Loechler, Edward L (2003) Molecular modeling of the major benzo[a]pyrene N2-dG adduct in cases where mutagenesis results are known in double stranded DNA. Mutat Res 529:59-76

Lee, Chiu Hong; Chandani, Sushil; Loechler, Edward L (2002) Molecular modeling of four stereoisomers of the major B[a]PDE adduct (at N(2)-dG) in five cases where the structure is known from NMR studies: molecular modeling is consistent with NMR results. Chem Res Toxicol 15:1429-44

Kozack, R; Seo, K Y; Jelinsky, S A et al. (2000) Toward an understanding of the role of DNA adduct conformation in defining mutagenic mechanism based on studies of the major adduct (formed at N(2)-dG) of the potent environmental carcinogen, benzo[a]pyrene. Mutat Res 450:41-59

Kozack, R E; Shukla, R; Loechler, E L (1999) A hypothesis for what conformation of the major adduct of (+)-anti-B[a]PDE (N2-dG) causes G-->T versus G-->A mutations based upon a correlation between mutagenesis and molecular modeling results. Carcinogenesis 20:95-102

Kozack, R E; Loechler, E L (1999) Molecular modeling of the major adduct of (+)-anti-B[a]PDE (N2-dG) in the eight conformations and the five DNA sequences most relevant to base substitution mutagenesis. Carcinogenesis 20:85-94