Modeling of Halogen-Protein Interactions in Co-Solvent Molecular Dynamics Simulations

Co-solvent molecular dynamics (MD) simulations have recently become successful approaches in structure-based drug design but neglect important interactions such as halogen bonding. To be able to successfully model compound libraries containing halogenated ligands using co-solvent simulations, we investigate the use of halogenated benzene probes in co-solvent simulations on the two test systems human cathepsin L (hCatL) and the Y220C mutant of the tumor suppressor p53 (p53-Y220C). Our studies demonstrate that halogenated benzene probes indeed can unambiguously identify halogen-bonding interaction sites in the binding pocket and show superior correlation and ranking performance compared to standard co-solvent approaches.