Conversely, in chemical proteomics the promiscuity of electrophilic fragments is a feature that allows the identification of potentially modifiable residues across a proteome. Nonetheless, structure-based modeling can be critical here, for example in disambiguating which residue is labeled in a peptide, or which enantiomer of a racemic probe may be more active for further development. Modeling may also provide rational bases for the selectivity across probes for a given site, which can improve the SAR information extracted from the original proteomic experiment. This interest in TCIs has been accompanied by a resurgence of interest in computational methods that can model such inhibitors, which come with unique modeling challenges . Existing methods tend to focus on the evaluation of the end-point of the reaction, modeling the ligand in the bound state, such as the tethered or biased (or constrained) approaches . More computationally expensive methods supplement these models with free energy calculations . These methods are suitable for the analysis of well-defined sets of molecules into wellcharacterized binding sites but are not ideal for binding sites prediction across nucleophilic residues in a protein, let alone proteomes. For that, an ideal method should be capable of predicting both the correct residue for modification and the optimal reactive ligand(s). In this work, we present the formalization of the reactive docking method, which was specifically designed to address both challenges. This method uses a modified version of the AutoDock4 standard force field which modifies the near attack conformation (NAC, Fig. ), the last ground state geometry preceding the transition state geometries, with a decreased equilibrium distance for the reactive atoms. This species was chosen to model the ligand-target interaction because it represents an essential thermodynamic checkpoint for the reaction while containing minimal geometric perturbations to the ligand or target structures. With this model, the ligand is docked in the unmodified state prior to the reaction, with the reactive warhead still intact. Another advantage of modeling a nearattack conformation-like a NAC-like state is that, as a ground state model, no expensive QM calculations are required to determine the ligand and receptor geometries, minimizing the domain knowledge required to parameterize a new reaction class. Despite the geometric simplicity of this model, it serves as an essential step in the reaction pathway. The AutoDock standard force field estimates free energy of binding using the following equation for any pairwise interaction (i,j):