The 3-dimensional structure of anticancer drug-DNA complexes determined by X-ray crystallography

我们的主要目标是发现抗癌药物如何与DNA相互作用的分子细节，以及这些相互作用与非活性化学相关化合物的不同之处。我们建议利用X射线结晶学和我们开发的确定一类抗肿瘤活性药物DNA络合物三维结构的成功方法来研究其他临床或科学上重要的DNA插层抗癌药物的络合物。这些药物通过毒化DNA结合酶拓扑异构酶来发挥作用。结晶学分析将在原子水平上给我们明确的答案，即药物与DNA结合的确切方式，以及这种结合在抗肿瘤活性化合物和非活性化合物之间有何不同。我们认为，在原子水平上了解一类插层抗癌药物的DNA结合模式对于指导该类药物的设计是有价值的。

Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents act by poisoning the DNA binding enzyme topoisomerase. Crystallographic analysis will give us unequivocal answers at the atomic level as to the exact way in which the drug binds to DNA and how this binding differs between antitumour active and inactive compounds. We believe that a knowledge of the DNA binding mode of a class of intercalating anticancer drugs at the atomic level is valuable in guiding drug design within that class.