Structural Insights on the Role of Halogen Bonding in Protein MEK Kinase-Inhibitor Complexes

Kinases are enzymes that play a critical role in governing essential biological processes. Due to their pivotal involvement in cancer cell signaling, they have become key targets in the development of anti-cancer drugs. Among these drugs, those containing the 2,4-dihalophenyl moiety demonstrated significant potential. Here we show how this moiety, particularly the 2-fluoro-4-iodophenyl one, is crucial for the structural stability of the formed drug-enzyme complexes. Crystallographic analysis of reported kinase-inhibitor complex structures highlights the role of the halogen bonding that this moiety forms with specific residues of the kinase binding site. This interaction is not limited to FDA-approved MEK inhibitors, but it is also relevant for other kinase inhibitors, indicating its broad relevance in the design of this class of drugs. Crystal structures of protein kinase complexes with FDA-approved MEK inhibitors showcase the key role of halogen bonds in conferring specificity and affinity for binding halogenated molecules by this important class of biomacromolecules. image