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JP16

A New Approach to Drug Molecular Design based on Neural Network Analysis and Molecular Orbital Calculation : Molecular Modeling to Circumvent Cancer Drug Resistance Associated with ABCG2

○Sachiko Aida-Hyugaji（Information Technology Center, Tokai University），Jumma Nomura（Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology），Minoru Sakurai（Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology、Center for Biological Resources and Informatics, Tokyo Institute of Technology），Daisuke Tokushima （Fundamental Research Laboratories, NEC Corporation）， Toshikazu Takada（Fundamental Research Laboratories, NEC Corporation），Umpei Nagashima（National Institute of Advanced Industrial Science and Technology, Grid Technology Research Center），Hiroshi Nakagawa（Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology），Toshihisa Ishikawa（Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology）

Irinotecan (CPT-11) is a widely-used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I). However, overexpression of ABCG2 can confer cancer cells resistance to SN-38, that is, the active form of CPT-11. In the present study, to develop a platform for the molecular modeling to circumvent cancer drug resistance associated with ABCG2, we have characterized a total of fourteen new SN-38 analogues by some typical properties, which were evaluated by molecular orbital (MO) calculations and neural network (NN) QSAR technique. The NN was applied to estimate hydrophobic properties (LogP) of the analogues. Thereafter, the electrostatic potential (ESP) and the salvation free energy (dG) were evaluated by MO calculation. These indexes were found to be well correlated with the drug resistance ratio experimentally observed in ABCG2-overexpressing cells. It is suggested that hydrophilic analogues carrying OH- or NH2-groups are good substrates for ABCG2 and therefore exported from cancer cells. In contrast, SN-38 analogues with Cl atom have similar LogP values and high affinities toward the putative active site of ABCG2, however they were not substrates of ABCG2. From these results, it is strongly suggested that hydrogen bonds are critically involved in the transport mechanism of ABCG2.