CONFORMATIONS OF COMPLEXES BETWEEN PYRROLO[1,4]BENZODIAZEPINES AND DNA SEGMENTS
CONFORMATIONS OF COMPLEXES BETWEEN PYRROLO[1,4]BENZODIAZEPINES AND DNA SEGMENTS
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DOI：
10.1021/jm00162a012
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发表时间：
1986-12-01
影响因子：
7.3
通讯作者：
HOPFINGER, AJ
中科院分区：
文献类型：
--
作者：
REMERS, WA;MABILIA, M;HOPFINGER, AJ
分子力学程序 AMBER 在 CHEMLAB II 的协助下，用于模拟蒽霉素、茅霉素和新霉素 A 与 B 型构象中的六核苷酸双链体 d(GCATGC)2 的共价和非共价结合。当鸟嘌呤的 N2 处共价键合的结构以任一方向放置在小沟中时，具有良好的配合性。然而，能量分析显示侧链指向共价结合链的5''末端的方向是优选的。这种偏好与已发表的 NMR 研究一致。鸟嘌呤附近小沟中的蒽霉素非共价结合具有良好的拟合效果，螺旋几乎没有变形，并且配体的反应中心距离 N2 足够近，以便随后形成共价键。蒽霉素还在小沟中的腺嘌呤附近产生良好的非共价复合物，但在大沟中的结合降低了分散吸引力。茅屋霉素的结合与蒽霉素相似，但茅屋霉素较小的尺寸导致较低的结合能。新霉素非共价结合的特点是强静电相互作用，部分涉及 3-OH 基团，部分分子位于小沟之外。 AMBER 用于蒽霉素类似物的探索性设计，理论上该类似物可以与蒽霉素一样结合，但不会引起心脏毒性。进行了一项涉及蒽霉素、茅霉素和五核苷酸双链体 d(AAGAA/TTCTT) 的相关研究，以进一步评估 AMBER 预测序列特异性的能力。它指示了双链体小沟中朝向 5'' 的优选结合方向，但与非共价结合链的相互作用相当弱。这一预测与茅霉素的实验一致，显示双链体的分离以及药物向共价结合链的 5'' 端对齐。
The molecular mechanics program AMBER, assisted by CHEMLAB II, was used to model the covalent and noncovalent binding of anthramycin, tomaymycin, and neothramycin A to the hexanucleotide duplex d(GCATGC)2 in the B-form conformation. Structures covalently bonded at N2 of guanine gave excellent fits when placed in either direction in the minor groove. However, energy analysis showed a preference for the direction wherein the side chain points towards the 5'' end of the covalently bound strand. This preference agrees with published NMR studies. Noncovalent binding of anthramycin in the minor groove near guanine gave good fits with almost no distortion in the helix, and the reactive center of the ligand was close enough to N2 for subsequent covalent bond formation. Anthramycin also gave a good noncovalent complex near adenine in the minor groove, but binding in the major groove had decreased dispersion attractions. Binding of tomaymycin was similar to that of anthramycin, although the smaller size of tomaymycin resulted in less binding energy. Neothramycin noncovalent binding was characterized by strong electrostatic interactions, partly involving the 3-OH group, and by part of the molecule lying outside the minor groove. AMBER was used for the exploratory design of an anthramycin analogue that theoretically would bind as well as anthramycin but not cause cardiotoxicity. A related study involving anthramycin, tomaymycin, and the pentanucleotide duplex d(AAGAA/TTCTT) was undertaken to evaluate further the ability of AMBER to predict sequence specificity. It indicated a preferred direction of binding toward 5'' in the minor groove of the duplex, but rather weak interaction with the noncovalently bound strand. This prediction agreed with experiments on tomaymycin that showed separation of the duplex and alignment of the drug toward the 5'' end of the covalently bound strand.