Details of Grant 

EPSRC Reference:	EP/C013328/1
Title:	Fast, accurate calculations on transition metal-DNA complexes: pi-stacking and DNA intercalation
Principal Investigator:	Platts, Dr JA
Other Investigators:
Researcher Co-Investigators:
Project Partners:	University of Bristol
Department:	Chemistry
Organisation:	Cardiff University
Scheme:	Standard Research (Pre-FEC)
Starts:	01 October 2005	Ends:	30 September 2008	Value (£):	149,017
EPSRC Research Topic Classifications:	Biological & Medicinal Chem. Chemical Biology Drug Formulation & Delivery
EPSRC Industrial Sector Classifications:	Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Summary on Grant Application Form
DNA plays a key role in the functioning of all living things, and is therefore a popular target for drug therapy. Many classes of molecule have been designed to have an effect on DNA: one of the most promising of these are transition metal complexes. The archetypal DNA-targeting metal complex is cisplatin, cis-[Pt(Cl)2(NH3)2], the third most widely used anti-cancer drug in the world. Cisplatin covalently binds to DNA, cross-linking the double helix structure, hence preventing replication and even inducing cell death. While many complexes other than cisplatin have been shown to act in a similar manner, to date none has shown sufficient advantage over it to replace it as a drug. The search for new metal-based anti-cancer drugs is intense, and many strategies proposed, with particular emphasis on involving different modes of binding than formation of covalent bonds. One such mode is intercalation, in which the drug slots between adjacent DNA bases, held in place by so-called dispersion or pi-stacking forces. Such forces are difficult to describe theoretically, generally requiring accurate and time-consuming calculations. In this proposal, we set out methods to describe metal-based intercalating agents, and their interactions with DNA, in reasonable timescales without sacrificing accuracy. These methods will be used firstly to study how metal complexes interact with relatively small models of DNA, i.e. with one or two nucleic acid bases, then subsequently to model how they affect larger scale DNA structure and function.
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