Gallego J, Ortiz A R, de Pascual-Teresa B, Gago F
Department of Physiology and Pharmacology, University of Alcalá, Madrid, Spain.
J Comput Aided Mol Des. 1997 Mar;11(2):114-28. doi: 10.1023/a:1008018106064.
Molecular models of the complexes between actinomycin D and 14 different DNA hexamers were built based on the X-ray crystal structure of the actinomycin-d(GAAGCTTC)2 complex. The DNA sequences included the canonical GpC binding step flanked by different base pairs, nonclassical binding sites such as GpG and GpT, and sites containing 2,6-diamino-purine. A good correlation was found between the intermolecular interaction energies calculated for the refined complexes and the relative preferences of actinomycin binding to standard and modified DNA. A detailed energy decomposition into van der Waals and electrostatic components for the interactions between the DNA base pairs and either the chromophore or the peptidic part of the antibiotic was performed for each complex. The resulting energy matrix was then subjected to principal component analysis, which showed that actinomycin D discriminates among different DNA sequences by an interplay of hydrogen bonding and stacking interactions. The structure-affinity relationships for this important antitumor drug are thus rationalized and may be used to advantage in design of novel sequence-specific DNA-binding agents.
基于放线菌素 D 与 d(GAAGCTTC)₂ 复合物的 X 射线晶体结构，构建了放线菌素 D 与 14 种不同 DNA 六聚体之间复合物的分子模型。DNA 序列包括两侧为不同碱基对的经典 GpC 结合位点、非经典结合位点如 GpG 和 GpT，以及含有 2,6 - 二氨基嘌呤的位点。在为优化后的复合物计算的分子间相互作用能与放线菌素与标准和修饰 DNA 的相对结合偏好之间发现了良好的相关性。对每个复合物进行了 DNA 碱基对与抗生素的发色团或肽部分之间相互作用的范德华力和静电成分的详细能量分解。然后对所得能量矩阵进行主成分分析，结果表明放线菌素 D 通过氢键和堆积相互作用的相互作用来区分不同的 DNA 序列。因此，这种重要抗肿瘤药物的结构 - 亲和力关系得到了合理化解释，并可用于设计新型序列特异性 DNA 结合剂。
