We are investigating the specific molecular recognition of unusual DNA structures such as parallel duplexes, triplexes and quadruplexes by small molecules. There is some evidence suggesting that these types of structures may exist in vivo and they may represent unique targets for drug development. We are currently working on a dimeric hairpin quadruplex formed by two strands of d(G3T4G3) A series of high resolution NMR experiments has been carried out on this structure and we have refined the NMR NOESY data using restrained molecular dynamics in an effort to obtain a three-dimensional structure. This structure will serve as the starting point for a DOCK-based search of the Cambridge Crystallographic database for small ligands that preferentially bind DNA quadruplexes relative to DNA duplexes. We have also used the X-ray structure of a different folded quadruplex, [d(G4T4G4)]2 as the basis for a DOCK search targeting one of the grooves. This work has identified a ligand that forms a specific complex with this quadruplex and we are currently investigating its solution structure using 2D NMR. Much of our structure determination work as well as DOCK-based investigations relies heavily on the use of MidasPlus. For example, visual examination of all of our structures is carried out with MidasPlus, which can provide very helpful distance and angle information for any structure. The ability to work with several different molecules is of crucial importance in evaluating the binding of one molecule to another, as in our work on ligand binding to quadruplexes.
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