Reactive Docking: A Computational Method for High-Throughput Virtual Screenings of Reactive Species

We describe the formalization of the reactive docking
protocol,
a method developed to model and predict reactions between small molecules
and biological macromolecules. The method has been successfully used
in a number of applications already, including recapitulating large
proteomics data sets, performing structure–reactivity target
optimizations, and prospective virtual screenings. By modeling a near-attack
conformation-like state, no QM calculations are required to model
the ligand and receptor geometries. Here, we present its generalization
using a large data set containing more than 400 ligand–target
complexes, 8 nucleophilic modifiable residue types, and more than
30 warheads. The method correctly predicts the modified residue in
∼85% of complexes and shows enrichments comparable to standard
focused virtual screenings in ranking ligands. This performance supports
this approach for the docking and screening of reactive ligands in
virtual chemoproteomics and drug design campaigns.