How does a drug molecule find its target binding site?
How does a drug molecule find its target binding site?
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DOI：
10.1021/ja202726y
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发表时间：
2011-06-22
影响因子：
15
通讯作者：
Shaw, David E.
中科院分区：
文献类型：
--
作者：
Shan, Yibing;Kim, Eric T.;Eastwood, Michael P.;Dror, Ron O.;Seeliger, Markus A.;Shaw, David E.
尽管控制药物分子与蛋白质目标结合的热力学原理已经被很好地理解，但对这种结合发生的过程进行详细的实验表征已被证明是具有挑战性的。我们进行了相对较长的、无导向的分子动力学模拟，其中一个配体（抗癌药物达沙替尼或激酶抑制剂PP1）最初被放置在一个盒子里的随机位置，盒子里还含有一个已知与配体结合的蛋白质（Src激酶）。在这些模拟中，配体正确地识别了其目标结合位点，形成了一个与晶体学确定的结合结构几乎相同的复合物。模拟的轨迹提供了整个结合过程的连续的，原子水平的视图，揭示了持久的和值得注意的中间构象，并阐明了水分子的作用。我们采用的技术不需要预先知道结合位点的位置，可能在开发针对先前未发现的结合位点的变构抑制剂方面特别有用。
Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, detailed experimental characterization of the process by which such binding occurs has proven challenging. We conducted relatively long, unguided molecular dynamics simulations in which a ligand (the cancer drug dasatinib or the kinase inhibitor PP1) was initially placed at a random location within a box that also contained a protein (Src kinase) to which that ligand was known to bind. In several of these simulations, the ligand correctly identified its target binding site, forming a complex virtually identical to the crystallographically determined bound structure. The simulated trajectories provide a continuous, atomic-level view of the entire binding process, revealing persistent and noteworthy intermediate conformations and shedding light on the role of water molecules. The technique we employed, which does not assume any prior knowledge of the binding site’s location, may prove particularly useful in the development of allosteric inhibitors that target previously undiscovered binding sites.
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