CHARMM-GUI Covalent Ligand Docker as a Web-Based Molecular Docking Platform for Covalent Ligands

Covalent inhibitor research is an emerging topic in drug discovery because of its superior performance in specificity and inhibition effects. While molecular docking is a popular strategy in predicting and assessing ligand conformations or poses in receptor proteins, covalent ligand docking requires nontrivial preparation efforts as the ligand structure changes during the covalent complex formation. In order to facilitate molecular docking for covalent ligands, we have developed CHARMM-GUI Covalent Ligand Docker (CGUI-CLD), a new module for covalent ligand docking supported by AutoDock4. CGUI-CLD automates ligand preparation, supports ligand modification, implements docking simulations, and presents results through an intuitive user interface. A knowledge-based library built in CGUI-CLD currently supports 66 warheads and 8 amino acids, which can be used to automate the covalent ligand transformation from a prereaction to a postreaction adduct form seamlessly. Moreover, CHARMM-GUI High-Throughput Simulator is integrated for rapid generation of multiple molecular dynamics simulation systems. CGUI-CLD is expected to significantly reduce the unnecessary workload of covalent ligand docking and advance covalent ligand research.