Platinum-based antitumour drug ZD0473 was designed to reduce the cisplatin resistance to the tumor cells. In this paper, the mixed method of molecular mechanics and quantum chemistry, HF/lanl2dz// MM/uff and B3LYP/lanl2dz//6-31G*, are used to investigate the differences between four types of GG, 3′AG5′, 3′GA5′, and AA complexes, which are formed from four discrete DNA fragments recognized by ZD0473 and cisplatin. The results show that the binding interaction of both ZD0473 and cisplatin drugs with the GG base pair is much stronger than with other base pairs, namely the recognition capability of such drugs to the GG base pair is more considerable. Moreover, the interaction of four complexes of ZD0473 with DNA fragments is stronger than that of cisplatin with corresponding DNA fragments, which indicates the stronger binding capability of ZD0473 with DNA fragments and high antitumour activity of ZD0473. The main reason for easier forming of 3′GA5′ complex than the 3′AG5′ one is that the drug molecule prefers to bind with a single G base to form a monoligand compound firstly; then the configuration transformation from such monoligand compound to the bi-ligand one is limited.

The physical properties of adsorption and co-adsorption properties of CO and O-2 molecules on the MgO-supported Pd and Cu atoms have been studied at the DFT/B3LYP level of theory using the embedded cluster model. The calculations show that the supported Pd atom on the perfect surface is energetically more favorable for adsorbing a CO molecule than an O-2 molecule, with the respective binding energies of 206.5 vs. 84.8 kJ/mol. While such interactions on Pd atom located above an oxygen vacancy of the MgO(100) surface are very weak, due to significant amount of electron charge transferring from the vacancy to Pd atom. In contrast, the supported Cu atom on both types of surfaces prefers to adsorb O-2 molecule, instead of CO molecule, with the O-2 binding energies of 140 similar to 155 kJ/mol. It was found that the binding between the two-coadsorbates for CO+CO, CO+O-2, O-2+O-2 coadsorbed on the supported Pd atom on the perfect surface reduced the admolecule-Pd interactions by the reductive energies of 46 similar to 96 kJ/mol. Such reductions only for O-2+O-2 coadsorbed on the supported Cu atom on both surfaces are considerable with the reductive energies of 50 similar to 71 kJ/mol.

用分子力学与量子化学相结合的方法HF/lanl2dz//MM/uff及密度泛函方法B3LYP/lanl2dz//6-31g*探讨了ZD0473和顺铂分别与四个DNA片段识别所形成的GG,3′AG5′,3′GA5′及AA复合物的差异.结果表明,两种药物与GG碱基对的结合能力明显强于其他碱基对,从而显示出对GG碱基对更强的识别能力,而且由ZD0473构成的每种复合物的药物部分与DNA的相互作用能都比顺铂所形成的相应复合物的作用能大,说明ZD0473与DNA的结合能力强,抗肿瘤活性高.形成3′GA5′复合物而难以形成3′AG5′复合物的原因主要在于药物分子首先识别碱基G形成单配物,其次与单配物的结构变迁相关.

BBR3464 ( [{ trans-PtCl(NH3)(2)}(2)-mu-{trans-Pt(NH3)(2) (NH2(CH2)(6)NH2)(2)}](4+)) is currently in phase H clinical trials. It is of considerable interest to understand the patterns of DNA damage. Detailed studies about the geometrical and electrical configurations of the adduct of the trinuclear platinum compound and the 12-mer duplex 5'-d (ATATC, * TACATAT) (2)-3' was made with the molecular mechanics; molecular dynamics and quantum chemistry methods. The investigating results show that the coordinate bonds between platinum atoms of the trinuclear platinum complex and two N7's of *guanines four base apart on opposite DNA strands are the most important interaction and hydrogen bond interactions are critical factors influencing on the configuration of the adduct. The strong H8-H1' intraresiding electrostatic interaction for purine residues( G5, G17, A3, A7, A9, and A13) is consistent with a syn-conformation of the nucleoside unit, suggesting a delocalized structure and extensive conformational changes in solution. Since DNA is the major pharmacological target of platinum drugs, the unique structural characteristic may be related to the increased cytotoxicity and antitumor activity of BBR3464 as compared to cis-platin(cis-DDP).