Novel Procedure for Modeling Ligand/Receptor Induced Fit Effects

摘要

We present a novel protein-ligand docking method that accurately accounts for both ligand and receptor flexibility by iteratively combining rigid receptor docking (Glide) with protein structure prediction (Prime) techniques.While traditional rigid-receptor docking methods are useful when the receptor structure does not change substantially upon ligand binding,success is limited when the protein must be "induced" into the correct binding conformation for a given ligand.We provide an in-depth description of our novel methodology and present results for 21 pharmaceutically relevant examples.Traditional rigid-receptor docking for these 21 cases yields an average RMSD of 5.5 A.The average ligand RMSD for docking to a flexible receptor for the 21 pairs is 1.4 A; the RMSD is <=1.8 A for 18 of the cases.For the three cases with RMSDs greater than 1.8 A,the core of the ligand is properly docked and all key protein/ligand interactions are captured.