Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding
Reliable and Accurate Solution to the Induced Fit Docking Problem for Protein-Ligand Binding
复制标题
DOI：
10.1021/acs.jctc.1c00136
复制
发表时间：
2021-03-29
影响因子：
5.5
通讯作者：
Friesner, Richard A.
中科院分区：
文献类型：
--
作者：
Miller, Edward B.;Murphy, Robert B.;Friesner, Richard A.
我们提出了一个可靠的和准确的解决方案，结合基于配体的药效团对接，刚性受体对接，蛋白质结构预测与明确的溶剂分子动力学模拟诱导适合对接问题的蛋白质-配体结合。在详细的回顾性和前瞻性测试中，这种新的方法成功地确定了蛋白质-配体结合模式，在超过90%的交叉对接病例中，均方根偏差在2.5埃以内。我们进一步证明了这些预测的配体-受体结构足够准确，可以前瞻性地实现基于预测结构的药物发现，从而大大扩展了此类方法的适用范围。
We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking, rigid receptor docking, and protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective and prospective testing succeeded to determine protein-ligand binding modes with a root-mean-square deviation within 2.5 angstrom in over 90% of cross-docking cases. We further demonstrate these predicted ligand-receptor structures were sufficiently accurate to prospectively enable predictive structure-based drug discovery for challenging targets, substantially expanding the domain of applicability for such methods.