Fully Automated Molecular Mechanics Based Induced Fit Protein-Ligand Docking Method
Fully Automated Molecular Mechanics Based Induced Fit Protein-Ligand Docking Method
复制标题
DOI：
10.1021/ci800081s
复制
发表时间：
2008-10-01
影响因子：
5.6
通讯作者：
Venkatachalam, C. M.
中科院分区：
文献类型：
--
作者：
Koska, Juergen;Spassov, Velin Z.;Venkatachalam, C. M.
我们描述了一种将配体对接到蛋白质受体中同时允许蛋白质结合位点灵活性的方法。该方法采用了多步骤的程序，开始与蛋白质和配体构象的产生。然后通过计算结合位点热点来执行配体的初始放置。这个初始放置之后是蛋白质侧链细化阶段，该阶段对蛋白质柔性进行建模。该过程的最后一步是在刚性受体存在下配体位姿的所有能量最小化。因此，该算法在配体放置之前和之后的两个阶段对蛋白质的灵活性进行建模。我们验证了这种方法进行对接和交叉时钟研究的8个蛋白质系统的晶体结构可用于至少两个绑定配体。对于除了一个系统之外的所有系统，所得到的21个钟控蛋白质-配体复合物的rmsd值显示出2埃或更小的值。该方法对于高保真通量虚拟筛选研究具有两个关键优点。首先，110一旦在蛋白质中进行了初始结合位点选择，则在对接中需要用户干预。第二，对于给定的结合区域，初始蛋白质构象生成仅需要进行一次。此外，该方法可以根据正在执行对接的特定场景以各种方式定制。该方法的每个单独步骤都是完全独立的，因此可以直接探索高级工作流程的不同变体，以进一步提高准确性和性能。
We describe a method for docking a ligand into a protein receptor while allowing flexibility of the protein binding site. The method employs a multistep procedure that begins with the generation of protein and ligand conformations. An initial placement of the ligand is then performed by computing binding site hotspots. This initial placement is followed by a protein side-chain refinement stage that models protein flexibility. The final step of the process is all energy minimization of the ligand pose in the presence of the rigid receptor. Thus the algorithm models flexibility of the protein at two stages, before and after ligand placement. We validated this method by performing docking and cross clocking Studies of eight protein systems for which crystal Structures were available for at least two bound ligands. The resulting rmsd values of the 2 1 clocked protein-ligand complexes showed values of 2 angstrom or less For all but one of the systems examined. The method has two critical benefits for hi-fi throughput virtual screening studies. First, 110 User intervention is required in the docking once the initial binding site selection has been made in the protein. Second, the initial protein conformation generation needs to be performed only once for a given binding region. Also, the method may be customized in various ways depending on the particular scenario in which dockings are being performed. Each of the individual steps of the method is fully independent making it straightforward to explore different variants of the high level workflow to further improve accuracy and performance.