Platinum anticancer drugs molecular mechanism

Molecular mechanics and dynamics studies of metal-nucleotide and metal-DNA interactions to date have been limited almost exclusively to modeling the interactions involving platinum-based anticancer drugs. As with metal-amino-acid complexes, there have been surprisingly few molecular mechanics studies of simple metal-nucleotide complexes that provide a means of deriving reliable force field parameters. A study of bis(purine)diamine-platinum(II) complexes successfully reproduced the structures of such complexes and demonstrated how steric factors influenced the barriers to rotation about the Pt(II)-N(purine) coordinate bonds and interconversion of the head-to-head (HTH) to head-to-tail (HTT) isomers (Fig. 12.4)[2011. In the process, force field parameters for the Pt(II)/nucleotide interactions were developed. A promising new approach involving the use of ab-initio calculations to calculate force constants has been applied to the interaction between Pt(II) and adenine[202]. 

H. Harder, then in our laboratory but now at George Washington University, was responsible for these studies. He also checked that the synthesis of precursor molecules for DNA, and the transport of these across membranes was not responsible for the inhibition. He has more recently shown that the ability of the DNA to act as a template for new synthesis is strongly inhibited by the platinum drug. These results can be most reasonably explained by the hypothesis that the anticancer activity of the platinum drugs arises from a primary attack on DNA. The battle to discover the molecular mechanism of action was, therefore, joined on the field of metal complex interactions with DNA, and numerous other laboratories entered the fray. The booty has been rich, embarrasingly so. 

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