Quantitative structure activity and property study of platinum drugs

Computer-aided drug design (CADD) techniques have been applied to establish quantitative structure-activity relationships (QSAR) and quantitative structure- property relationships (QSPR) models. Although these techniques are widely used in organic drugs, new metal-based drugs were hindered from development for lack of metal parameters, such as potent new platinum drugs as a major group of drugs used in cancer treatment. The purpose of the present study, therefore, is to generate novel platinum parameters based on previous work and then set up the simple QSAR/QSPR model with predictive abilities.;Chemical hardness (eta), calculated by density functional theory (DFT), was firstly used as one of the chemical reactivity descriptors to set up the one descriptor 2D-QSAR model of platinum drugs. In this simple but promising model, the antitumour activities (log GI50) evaluated by National Cancer Institute (NCI) of structure-based groups containing normal sp 3 nitrogen and R,R-diamminecyclohexane (R,R-DACH) as the ligand showed good correlation. It was also demonstrated that silane and stereoisomers of DACH groups showed special patterns. This study also made use of the COMPARE program from NCI to evaluate the activity profile and the analysis of the data revealed these distinct patterns are influenced by the mechanism of the drugs.;To clarify the pattern of stereoisomers of the DACH group, new platinum parameters was introduced to the AMBER software successfully. Moreover, stereoisomers of the DACH group which formed 1,2-GG intrastrand cross-links with DNA were studied by molecular dynamics (MD) simulations using AMBER. The calculated binding energies between R,R-DACH-Pt, S,S-DACH-Pt and cis-DACHPt moieties and DNA revealed a strong correlation with antitumour activities. The result provided more clues to understand the biological interactions of chiral platinum drugs. DNA structure analysis indicated that DNA tolerated the distortion resulted in the different Pt-DNA adducts and various local and global structure distortions were found. Natural bond orbital (NBO) analysis of hydrogen bonding on Pt-DNA adducts at a AGGC site revealed that R,R-DACH-Pt moiety alleviated the repulsion by unwinding the DNA, whereas the S,S-DACH-Pt adduct avoided the interaction by distorting the H bonds of binding site basepairs. Hence, the structural differences of chiral platinum drug led to its distinct activity.;Finally, two 3D-QSAR and 3D-QSPR models obtained using Sybyl software. One was for demethylcantharidin (DMC) analogues as phosphatase 2A (PP2A) inhibitors. The other was describing the hydrophobicity of platinum drugs. In this research, the platinum atom was introduced to Sybyl and thus made it possible for the first time to use comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to investigate platinum drugs. All 3D models indicated good predictive ability and thus provided an effective method to design new potent platinum drugs.