In brief, 𝜟HvdW, 𝜟Hhbond, and 𝜟Hel ec are van der Waals, directional hydrogen bond, and electrostatic enthalpies, 𝜟St or is the torsional entropy, and 𝜟Gdesol v is the desolvation free energy (for a full description of all the terms see reference ). The standard force field is modified by adding a 13-7 potential 𝜟Hreact between the ligand reactive atom i* and the receptor reactive atom j* to represent incipient bond formation: where req represents the equilibrium distance (Å) and ε represents the equilibrium energy (kcal/mol). Like van der Waals and hydrogen bond potentials, the reactive potential is also softened according to the standard AutoDock force field description . As a result of this newly created pseudointeraction, atoms within two bonds of the two reactive atoms will be placed at distances shorter than their respective van der Waals equilibrium distances (Fig. ). To compensate for the tight proximity that this geometry would induce, the r_eq distances for pseudo 1-3 and 1-4 pairwise interactions around reactive atoms are scaled by factors W1, 3 and W1, 4, respectively, while any hydrogens bound to these atoms are ignored entirely from the pairwise calculation. Any atom beyond two bonds from the reactive atom pair is treated with default parameters. During docking, ligands are free to explore multiple binding modes including those not compatible with the formation of a covalent bond with the target residue, which is modeled as flexible . Once dockings are completed, the result with the best docking score is analyzed to measure the distance between ligand and residue reactive atoms, determining the outcome of the reaction (i.e.: covalent or not, Fig. ). This method was initially developed to model acrylamides and chloroacetamides reacting with cysteine thiols , then it was extended to model more warheads and residues and successfully applied to a variety of chemical proteomic tasks. In particular, it was used successfully to resolve ambiguity in reactive residues in ABPP experiments on human T cells , identifying the residue most likely to be modified based on structural data. The method has been extended and applied to other reactions, such as those involving SuFEx warheads , and used in an "inverse drug discovery" campaign targeting lysines and tyrosines in the human proteome . In addition, it has been used in focused drug design campaigns to model the reaction between SuFEx and serine residues in specific targets . In this work, the method is optimized and validated on a diverse dataset of targets (Fig. ) and warheads and reactions (Fig. ).