Evidence for C-Cl/C-Br···π Interactions as an Important Contribution to Protein-Ligand Binding Affinity

摘要

The modulation of pharmacokinetic properties by the introduction of halogen atoms into lead structures is a well-established strategy for lead optimization. This includes the blocking of metabolically labile positions of a particular scaffold and the tuning of physicochemical properties to influence membrane permeability and tissue distribution of drug candidates. In particular, the role of organic fluorine atoms, which are often considered as a bioisosteric hydrogen or oxygen replacement, has been extensively investigated on a molecular level, including its effects on protein-ligand interactions in hydrophobic pockets and its involvement as interaction partner.In addition, increasing experimental evidence indicates that organic chlorine and bromine atoms are favorably involved in discrete noncovalent dipolar protein-ligand interactions and thus contribute significantly to binding affinity in molecular recognition.However, much less is known about the nature of nonbonding interactions of organic chlorine and bromine atoms with hydrophobic aromatic protein areas and their contribution to binding affinities.