Role and nature of halogen bonding in inhibitor⋅⋅⋅receptor complexes for drug discovery: casein kinase-2 (CK2) inhibition as a case study

Halogen bond effectively contributes to inhibitor⋅⋅⋅receptor binding affinity. Several critical questions remain about the nature of halogenated inhibitor⋅⋅⋅receptor interactions. In the current study, the role and nature of the halogen bonding in halo-derivatives of benzimidazole in complex with casein kinase-2 (CK2) protein was clarified from molecular mechanical perspective. The molecular mechanics/generalized Born surface area (MM-GBSA) binding energy was calculated for the energetically minimized halogenated inhibitor⋅⋅⋅CK2 complexes and compared to the experimental data. The results were further assessed with the help of halogen bond test (–σ-hole test) at AMBER-molecular mechanical (MM) level. A molecular mechanical estimation of the halogen’s atomic parameter contribution (e.g., electrostatic and van der Waals contributions) was performed to characterize the nature of the halogen bonding using our previously proposed atomic parameter contribution to molecular interaction (APCtMI) approach. In accordance with the results, the inhibitor⋅⋅⋅CK2 binding energy increased with increasing the charge value of halogen’s σ-hole in the order iodo- > bromo- > chloro-derivative. One unanticipated finding was the disability of chloro-derivative to form a halogen bonding with the hinge region of the CK2 protein. APCtMI results revealed that halogen’s negative charge has no significant contribution to the total MM-GBSA binding energy. Furthermore, van der Waals interactions have a significant impact on the halogenated inhibitors⋅⋅⋅receptor binding energy. The APCtMI results were assessed by evaluating the binding energies of several hydrogen-substituted derivatives of tetrabromo-benzimidazole with CK2. These results should further the role of halogens for the purpose of drug discovery and development.