The relaxed complex method: Accommodating receptor flexibility for drug design with an improved scoring scheme
The relaxed complex method: Accommodating receptor flexibility for drug design with an improved scoring scheme
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DOI：
10.1002/bip.10218
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发表时间：
2003-01-01
期刊：
影响因子：
2.9
通讯作者：
McCammon, JA
中科院分区：
文献类型：
--
作者：
Lin, JH;Perryman, AL;McCammon, JA
用于药物设计的新计算方法的扩展，“松弛复合物”方法（J. H. Lin，L. L.佩里曼Schames和J. A. McCammon，Journal of the American Chemical Society，2002，vol.24，pp. 5632-5633），其适应受体柔性。这种放松的复合物方法认识到，配体可以结合到构象中很少发生的动态受体。我们已经表明，配体-酶结合模式是非常敏感的酶的构象，我们的方法是能够找到最好的配体酶复合物。快速对接作为一种有效的初始过滤方法，筛选无数的对接模式到有限的集合，然后用MM/PBSA（分子力学/泊松玻尔兹曼表面积）方法进行更准确的评分，以找到最佳的配体-受体复合物。MM/PBSA评分一致表明，与X射线晶体学复合物中观察到的结合模式最相似的计算结合模式是自由能最低的结合模式。(C)2002 Wiley Periodicals，Inc.
An extension of the new computational methodology for drug design, the "relaxed complex" method (J.-H. Lin, A. L. Perryman, J. R. Schames, and J. A. McCammon, Journal of the American Chemical Society, 2002, vol. 24, pp. 5632-5633), which accommodates receptor flexibility, is described. This relaxed complex method recognizes that ligand may bind to conformations that occur only rarely in the dynamics of the receptor. We have shown that the ligand-enzyme binding modes are very sensitive to the enzyme conformations, and our approach is capable of finding the best ligand enzyme complexes. Rapid docking serves as an efficient initial filtering method to screen a myriad of docking modes to a limited set, and it is then followed by more accurate scoring with the MM/PBSA (Molecular Mechanics/Poisson Boltzmann Surface Area) approach to find the best ligand-receptor complexes. The MM/PBSA scorings consistently indicate that the calculated binding modes that are most similar to those observed in the x-ray crystallographic complexes are the ones with the lowest free energies. (C) 2002 Wiley Periodicals, Inc.