D. E. Shaw Research, New York, New York 10036, USA.
J Am Chem Soc. 2011 Jun 22;133(24):9181-3. doi: 10.1021/ja202726y. Epub 2011 May 13.
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.
尽管控制药物分子与其蛋白质靶标结合的热力学原理已经得到很好的理解，但详细的实验表征证明，药物分子与蛋白质靶标结合的过程极具挑战性。我们进行了相对较长的、无引导的分子动力学模拟，在这些模拟中，最初将配体（癌症药物达沙替尼或激酶抑制剂 PP1）放置在一个盒子内的随机位置，该盒子内还包含一个已知与该配体结合的蛋白质（Src 激酶）。在这些模拟中的几个中，配体正确地识别出了其靶标结合位点，形成了一个几乎与晶体确定的结合结构完全相同的复合物。模拟轨迹提供了整个结合过程的连续、原子级视图，揭示了持久且值得注意的中间构象，并阐明了水分子的作用。我们所采用的技术不假设对结合位点位置的任何先验知识，这可能在开发靶向以前未发现的结合位点的变构抑制剂方面特别有用。
