Target flexibility: an emerging consideration in drug discovery and design.
Target flexibility: an emerging consideration in drug discovery and design.
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DOI：
10.1021/jm800562d
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发表时间：
2008-10-23
影响因子：
7.3
通讯作者：
Sotriffer CA
中科院分区：
文献类型：
--
作者：
Cozzini P;Kellogg GE;Spyrakis F;Abraham DJ;Costantino G;Emerson A;Fanelli F;Gohlke H;Kuhn LA;Morris GM;Orozco M;Pertinhez TA;Rizzi M;Sotriffer CA
基于结构的药物发现在药物化学中起着重要的作用，几乎始于Perutz， Kendrew和同事在近原子分辨率下描述了肌红蛋白和血红蛋白的第一个x射线晶体结构。2-5尽管大多数基于结构的药物设计（sdbda）和大多数分子建模都只使用静态结构，但灵活性的重要性立即被认识到：血红蛋白有两种截然不同的结构，“紧张”和“松弛”，这取决于其氧合作用，尽管近年来已经报道了一系列具有不同三级结构构象的松弛血红蛋白结构。事实上，所有的蛋白质本质上都是灵活的系统。这种灵活性通常是功能所必需的（如血红蛋白）。蛋白质具有内在的能力，在自然状态下进行功能相关的构象转变7,8在时间和空间的广泛尺度上。9在腺苷酸激酶中，由于核苷酸“盖子”的运动而引起的大构象变化（总的催化翻转率限制10,11）与
Structure-based drug discovery has played an important role in medicinal chemistry, 1 beginning nearly when the first X-ray crystal structure of the myoglobin and hemoglobin proteins at near-atomic resolution were described by Perutz, Kendrew and colleagues. 2-5 Even though only static structures were (and still generally are) used for most structure-based drug design (SBDDa) and indeed most molecular modeling, the importance of flexibility was recognized immediately: hemoglobin has two rather different structures,“tense” and “relaxed”, depending on its oxygenation, although in recent years a family of relaxed hemoglobin structures with different tertiary structure conformations have been reported. 6 In fact, all proteins are inherently flexible systems. This flexibility is frequently essential for function (eg, as in hemoglobin). Proteins have an intrinsic ability to undergo functionally relevant conformational transitions under native state conditions7, 8 on a wide range of scales, both in time and space. 9 In adenylate kinase large conformational changes due to movements of the nucleotide “lids”(ratelimiting for overall catalytic turnover10, 11) are “linked” with
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影响因子：
3.5
作者：
Bottegoni, Giovanni;Kufareva, Irina;Abagyan, Ruben
通讯作者：
Abagyan, Ruben
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
7.3
作者：
Cioffi, Marina;Hunter, Christopher A.;Spitaleri, Andrea
通讯作者：
Spitaleri, Andrea
影响因子：
3.4
作者：
Chen, W;Chang, CE;Gilson, MK
通讯作者：
Gilson, MK
影响因子：
3.4
作者：
Atilgan, AR;Durell, SR;Bahar, I
通讯作者：
Bahar, I