Covalent docking in CDOCKER.

Targeted covalent inhibitors (TCIs) are considered to be an important component in the toolbox of drug discovery and about 30% of currently marketed drugs are TCIs. Although these drugs raise concerns about toxicity, their high potencies and prolonged effects result in less-frequent drug dosing and wide therapeutic margins for patients. This leads to increased interests in developing new computational methods to identify novel covalent inhibitors. The implementation of successful in silico docking algorithms have the potential to provide significant savings of time and money in the discovery of lead compounds. In this paper, we describe the implementation and testing of a covalent docking methodology in Rigid CDOCKER and the optimization of the corresponding physics-based scoring function with an additional customizable covalent bond grid potential which represents the free energy change of bond formation between the ligand and the receptor. We optimize the covalent bond grid potential for different common covalent bond formation reaction in TCIs. The average runtime for docking one covalent compound is 15 minutes which is comparable or faster than other well-established covalent docking methods. We demonstrate comparable top rank accuracy compared with other covalent docking algorithms using the pose prediction benchmark dataset for covalent docking algorithms developed by the Keserű group. Finally, we construct a retrospective virtual screening benchmark dataset containing 8 different receptor targets with different covalent bond formation reactions. To our knowledge, this is the largest dataset for benchmarking covalent docking methods. We show that our new covalent docking algorithm has the ability to identify lead compounds among a large chemical space. The largest AUC value is 0.909 for the target receptor CATK and the warhead chemistry of the covalent inhibitors is addition to the aldehyde functionality.