Gresh N, Kahn P H
Institut de Biologie Physico-Chimique, Paris, France.
J Biomol Struct Dyn. 1990 Apr;7(5):1141-60. doi: 10.1080/07391102.1990.10508552.
Mitoxantrone (MTX) is a recently synthesized antitumor intercalative molecule, currently in use in chemotherapy. Previous theoretical computations showed that the base pair selectivity of MTX is limited to the sole two base-pair sequence making up the intercalation site. In order to further extend the recognition site, we undertook, by means of theoretical computations, the design of novel MTX derivatives, in which the terminal hydroxyl group of each side chain is esterified with oligopeptides. We compare in the present study the binding affinities of two derivatives, depsiGly-Lys(D) and depsiGly-Gly-Orn(L), for the palindromic sequences d(CCCGGG)2, d(GCCGGC)2, d(GGCGCC)2, and d(CGCGCG)2. Major groove binding of the oligopeptide arms was shown to be significantly more favourable than either minor groove binding, or binding to the sole phosphate groups. With the two arms adopting two antiparallel directions, two distinct arrangements were investigated in the major groove: (a) the two oligopeptides are brought closer together by means of two hydrogen bonds involving the backbone of their second residue in a beta-sheet like arrangement; (b) the two arms are remote from each other so as to reduce their mutual electrostatic repulsion. Whatever the disposition, the optimal binding configurations were invariably found to be those in which the cationic side chains of the terminal residues chelate N7/O6 of two successive guanines, whenever present on a given strand. A distinct energetical preference for arrangement (a) was obtained with the depsiGly-Gly-Orn(L) derivative. Replacement of the central Gly residue by a Cys one, as in the sequence depsiGly-Cys-Orn(L), was proposed subsequently, so as to further stabilize such a beta-sheet arrangement by means of a disulfide bridge between the two Cys residues. The two investigated compounds were shown to preferentially bind sequences d(CCCGGG)2 and d(GCCGGC)2, with a tetrameric core CCGG rather than sequences d(GGCGCC)2 and d(CGCGCG)2, with a tetrameric core GCGC.
米托蒽醌（MTX）是一种最近合成的抗肿瘤嵌入分子，目前用于化疗。先前的理论计算表明，MTX的碱基对选择性仅限于构成嵌入位点的唯一两个碱基对序列。为了进一步扩展识别位点，我们通过理论计算进行了新型MTX衍生物的设计，其中每个侧链的末端羟基与寡肽酯化。在本研究中，我们比较了两种衍生物depsiGly-Lys(D)和depsiGly-Gly-Orn(L)与回文序列d(CCCGGG)2、d(GCCGGC)2、d(GGCGCC)2和d(CGCGCG)2的结合亲和力。结果表明，寡肽臂的大沟结合明显比小沟结合或仅与磷酸基团结合更有利。由于两条臂采取两个反平行方向，因此在大沟中研究了两种不同的排列方式：(a) 两条寡肽通过涉及它们第二个残基主链的两个氢键以类似β-折叠的排列方式靠得更近；(b) 两条臂彼此远离以减少它们之间的静电排斥。无论何种排列方式，最佳结合构型总是那些末端残基的阳离子侧链螯合两条连续鸟嘌呤的N7/O6的构型，只要它们出现在给定链上。对于depsiGly-Gly-Orn(L)衍生物，排列方式(a)具有明显的能量偏好。随后有人提出，用Cys取代中心Gly残基，如在序列depsiGly-Cys-Orn(L)中，以便通过两个Cys残基之间的二硫键进一步稳定这种β-折叠排列。结果表明，所研究的两种化合物优先结合具有四聚体核心CCGG的序列d(CCCGGG)2和d(GCCGGC)2，而不是具有四聚体核心GCGC的序列d(GGCGCC)2和d(CGCGCG)2。
