Flexible water docking and virtual screening using PLANTS combined with tuned water selection criteria

Docking and virtual screening including flexible water molecules at the ligand-receptor interface have been considered a difficult task. The task is mainly challenged by how and which water molecules are selected and how to keep water flexible during docking process. In this study, we have assessed the docking performance including flexible water molecules using PLANTS docking package, providing a potential resolution to the efficient virtual screening including flexible water molecules. To enable the efficient assessment, a set of selection criteria of water molecules within both the holo and apo structures was applied. The water molecules were selected from both crystal resolved water position and 3D-RISM calculations. Good correlation was demonstrated between the two and an ideal amount of water molecules can be preserved. Moreover, the selection procedures are also applicable to apo binding site, which allows further feasibility. We have demonstrated improved docked poses after inclusion of flexible water assessed using three test sets, two of which derived from CCDC-Astex “clean” list and DUD-E database, and an additional apo test set. The performance of virtual screening was also assessed using several testing systems.