Hill G C, Remers W A
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arizona, Tucson 85721.
J Med Chem. 1991 Jul;34(7):1990-8. doi: 10.1021/jm00111a011.
The binding of Saframycin A to the octanucleotide duplex d(GATGCATC)2 was investigated using molecular dynamics. For covalent binding at N2 of the central guanine, only the R configuration at the alkylating carbon (C7) was permitted for B DNA and the 3' direction in the minor groove was preferred by 50.6 kcal/mol. The dihydroquinone form of saframycin A gave stronger binding than the quinone, in agreement with the literature. Addition of solvent and counterions made no significant change in the geometry model. The proposed mechanism of DNA alkylation, involving iminium ion intermediates from the dihydroquinone or quinone, was investigated by modeling these species. They gave models with good net binding enthalpies, and C7 was in close proximity to N2 of guanine. The noncovalent binding of saframycin A and its dihydroquinone in the vicinity of guanine also was favorable in the 3' direction.
使用分子动力学研究了沙弗拉霉素A与八核苷酸双链体d(GATGCATC)2的结合。对于中心鸟嘌呤N2处的共价结合，B型DNA仅允许烷基化碳（C7）处的R构型，且小沟中的3'方向比其他方向更受青睐，优势为50.6千卡/摩尔。与文献一致，沙弗拉霉素A的二氢醌形式比醌形式具有更强的结合力。添加溶剂和抗衡离子对几何模型没有显著影响。通过对这些物种进行建模，研究了涉及二氢醌或醌产生的亚胺离子中间体的DNA烷基化机制。它们给出了具有良好净结合焓的模型，且C7靠近鸟嘌呤的N2。沙弗拉霉素A及其二氢醌在鸟嘌呤附近的非共价结合在3'方向上也是有利的。
