Solution structure of 2-(pyrido[1,2-e]purin-4-yl)amino-ethanol intercalated in the DNA duplex d(CGATCG)(2)

The solution structure of the complex formed between d(CGATCG)(2) and 2-(py rido[1,2-e]purin-4-yl)amino-ethanol. a new antitumor drug under design, has been resolved using NMR spectroscopy and restrained molecular dynamic simu lations. The drug molecule intercalates between each of the CpG dinucleotid e steps with its side chain lying in the minor groove. Analysis of NMR data establishes a weak stacking interaction between the intercalated ligand an d the DNA bases; however, the drug/DNA affinity is enhanced by a hydrogen b ond between the hydroxyl group of the end of the intercalant side chain and the amide group of guanine G6. Unrestrained molecular dynamic simulations performed in a water box confirm the stability of the intercalation model. The structure of the intercalated complex enables insight into the structur e-activity relationship, allowing rationalization of the design of new anti neoplasic agents.