The paper describes the development and release of AutoDock4, an automated docking software that incorporates limited receptor flexibility, along with its graphical user interface, AutoDockTools. AutoDock4 uses a grid-based method for rapid evaluation of binding energies and a Lamarckian genetic algorithm for conformational searching. The software also supports flexible modeling of specific receptor sidechains to address receptor motion upon ligand binding. The authors report on several tests, including redocking experiments with 188 diverse ligand-protein complexes and cross-docking experiments with 87 HIV protease complexes using flexible sidechains. They also discuss methods for analyzing covalently-bound ligands, using both grid-based and flexible sidechain techniques. The results show that AutoDock4 successfully docks most complexes with limited receptor flexibility but struggles with higher flexibility. The paper highlights the importance of grid-based energy evaluation and the challenges of incorporating receptor flexibility, suggesting future improvements in energetic functions and hierarchical approaches.The paper describes the development and release of AutoDock4, an automated docking software that incorporates limited receptor flexibility, along with its graphical user interface, AutoDockTools. AutoDock4 uses a grid-based method for rapid evaluation of binding energies and a Lamarckian genetic algorithm for conformational searching. The software also supports flexible modeling of specific receptor sidechains to address receptor motion upon ligand binding. The authors report on several tests, including redocking experiments with 188 diverse ligand-protein complexes and cross-docking experiments with 87 HIV protease complexes using flexible sidechains. They also discuss methods for analyzing covalently-bound ligands, using both grid-based and flexible sidechain techniques. The results show that AutoDock4 successfully docks most complexes with limited receptor flexibility but struggles with higher flexibility. The paper highlights the importance of grid-based energy evaluation and the challenges of incorporating receptor flexibility, suggesting future improvements in energetic functions and hierarchical approaches.