A fast flexible docking method using an incremental construction algorithm
A fast flexible docking method using an incremental construction algorithm
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DOI：
10.1006/jmbi.1996.0477
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发表时间：
1996-08-23
影响因子：
5.6
通讯作者：
Klebe, G
中科院分区：
文献类型：
--
作者：
Rarey, M;Kramer, B;Klebe, G
我们提出了一种自动对接有机配体到蛋白质结合位点的方法。该方法可用于特定蛋白质配体的设计过程。它结合了一个适当的模型的物理化学性质的停靠分子和有效的方法来采样配体的构象空间。如果配体是柔性的，它可以采用多种不同的构象。构象空间中的每一个这样的最小值都是配体在络合状态下构象的潜在候选者。我们的对接方法在离散模型的基础上对配体的构象空间进行采样，并使用树搜索技术将配体增量放置到活性位点。为了将配体的第一个片段放入蛋白质中，我们使用了基于计算机视觉的散列技术。增量构造算法基于贪婪策略，结合有效的重叠检测和新交互搜索方法。我们提出了19个配合物的结果，其中结合几何已结晶学确定。所有考虑的配体在当前工作站最多停靠三分钟。实验观察到的配体结合模式在0.5 ~ 1.2埃的均方根偏差范围内得到了再现。它几乎总是在计算出的最高级构象中被发现。(C) 1996学术出版社有限公司
We present an automatic method for docking organic ligands into protein binding sites. The method can be used in the design process of specific protein ligands. It combines an appropriate model of the physico-chemical properties of the docked molecules with efficient methods for sampling the conformational space of the ligand. If the ligand is flexible, it can adopt a large variety Of different conformations. Each such minimum in conformational space presents a potential candidate for the conformation of the ligand in the complexed state. Our docking method samples the conformation space of the ligand on the basis of a discrete model and uses a tree-search technique for placing the ligand incrementally into the active site. For placing the first fragment of the ligand into the protein, we use hashing techniques adapted from computer vision. The incremental construction algorithm is based on a greedy strategy combined with efficient methods for overlap detection and for the search of new interactions. We present results on 19 complexes of which the binding geometry has been crystallographically determined. All considered ligands are docked in at most three minutes on a current workstation. The experimentally observed binding mode of the ligand is reproduced with 0.5 to 1.2 Angstrom rms deviation. It is almost always found among the highest-ranking conformations computed. (C) 1996 Academic Press Limited.