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

Area of Science:

• Computational Chemistry
• Structural Biology
• Drug Discovery

Background:

• The reactive docking protocol models reactions between small molecules and biological macromolecules.
• Existing applications include proteomics data analysis, structure-reactivity optimization, and virtual screening.
• The protocol models a near-attack conformation-like state, eliminating the need for quantum mechanics calculations for ligand and receptor geometries.

Purpose of the Study:

• To present a generalized and formalized reactive docking protocol.
• To validate the protocol using a large dataset of ligand-target complexes, residue types, and warheads.
• To assess the protocol's performance in predicting modified residues and ranking reactive ligands.

Main Methods:

• Formalization of the reactive docking protocol.
• Utilizing a dataset of over 400 ligand-target complexes.
• Incorporating 8 nucleophilic modifiable residue types and over 30 warheads.
• Modeling near-attack conformation-like states without requiring QM calculations.

Main Results:

• The generalized protocol correctly predicts the modified residue in approximately 85% of complexes.
• The method demonstrates enrichment factors comparable to standard focused virtual screenings in ranking ligands.
• Successful application in recapitulating large proteomics datasets and structure-reactivity target optimizations.

Conclusions:

• The formalized reactive docking protocol is a robust method for modeling and predicting reactions.
• The protocol's performance supports its use in virtual chemoproteomics and drug design.
• This approach facilitates the docking and screening of reactive ligands for therapeutic development.