Rapid flexible docking using a stochastic rotamer library of ligands.

Existing flexible docking approaches model the ligand and receptor flexibility either separately or in a loosely coupled manner, which captures the conformational changes inefficiently. Here, we propose a flexible docking approach, MedusaDock, which models both ligand and receptor flexibility simultaneously with sets of discrete rotamers. We developed an algorithm to build the ligand rotamer library "on-the-fly" during docking simulations. MedusaDock benchmarks demonstrate a rapid sampling efficiency and high prediction accuracy in both self- (to the cocrystallized state) and cross-docking (to a state cocrystallized with a different ligand), the latter of which mimics the virtual screening procedure in computational drug discovery. We also perform a virtual screening test of four flexible kinase targets, including cyclin-dependent kinase 2, vascular endothelial growth factor receptor 2, HIV reverse transcriptase, and HIV protease. We find significant improvements of virtual screening enrichments when compared to rigid-receptor methods. The predictive power of MedusaDock in cross-docking and preliminary virtual-screening benchmarks highlights the importance to model both ligand and receptor flexibility simultaneously in computational docking.