Duocarmycins binding to DNA explored by molecular simulation

Duocarmycins are a potent class of antitumor agents. Their activity arises by their covalent binding to adenine nucleobases of DNA. We use classical mol. dynamics and hybrid (QM/MM) Car-Parrinello mol. dynamics simulations to study non-covalent and covalent binding of three duocarmycins with different reactivities, namely DSA, DSI and NBOC-DSA. Reactions in water are explored for NBOC-DSA with adenine and simple model reactants. Our calcns. suggest that: (i) Non-covalent drug binding does not significantly perturb the DNA structure. (ii) The exptl. obsd. DNA catalytic power might be due, at least in part, to a polarization of the biomol. scaffold over the drugs. Instead, our calcns. do not support the \"shape induced activation\" mechanism, in which the conformational properties of the drug play a pivotal role for catalysis (5). (iii) The chem. nature of the drug influences the structure of the drug-DNA adduct, thus affecting the reactivity of the initial complex. (iv) The functional groups of the drugs affect the intrinsic reactivity of the compd. [on SciFinder (R)]

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Abstracts of Papers, 229th ACS National Meeting, San Diego, CA, United States, March 13-17, 2005, COMP-321

 Record created 2006-02-27, last modified 2018-03-17

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