What Can Be Learnt from Computer-Generated Models of Interactions Between DNA and Pt(II) Based Anti-Cancer Drugs?

Abstract

The use of computer-generated models to study the interactions between Pt(II) based anti-cancer drugs and their putative target, DNA, is described and critically analyzed. Computer-generated models have been used to gain insight into the factors which may mediate binding and influence anti-cancer activity. The emphasis has been on the distortions the binding of cisplatin causes in the DNA structure and on the hydrogen bonding and non-bonding interactions between the bound cisplatin moiety and the DNA. Computer-generated models have also been used to investigate why cisplatin does not bind to certain base sequences and hence have led to the design of compounds with potentially different binding specificities to those of cisplatin. Possible interactions between the new bisplatinum class of drugs and DNA have been modeled to determine how these drugs might bind.

The use of modeling to design new Pt(II)-based drugs is at present in its infancy. Strategies for the design of new compounds which might prove fruitful are outlined. Limitations to modeling and design approaches are discussed as is their use in conjunction with structural data from NMR spectra.

Key Words:

• Pt anti-cancer drugs
• cisplatin
• molecular modeling
• molecular mechanics