Competition between electrostatic interactions and halogen bonding in the protein–ligand system: structural and thermodynamic studies of 5,6-dibromobenzotriazole-hCK2α complexes

• DOI: 10.1038/s41598-022-23611-0
• Publication Date: 2022-11-08T12:09:39Z
• Authors: Maria Winiewska-S...; Honorata Czapinska; Magdalena Kaus-Dr...; Anna Fricke; Kinga Mieczkowska; Michał Dadlez; Matthias Bochtler; Jarosław Poznański
• Keywords: Isothermal Titration Calorimetry; Halogen bond

Abstract CK2 is a member of the CMGC group eukaryotic protein kinases and cancer drug target. It can be efficiently inhibited by halogenated benzotriazoles benzimidazoles. Depending on scaffold, substitution pattern, pH, these compounds are either neutral or anionic. Their binding poses dictated hydrophobic effect (desolvation) tug war between salt bridge/hydrogen bond (to K68) halogen bonding E114 V116 backbone oxygens). Here, we test idea that might controllable pH for ligands with near-neutral pK , using conditionally anionic 5,6-DBBt constitutively TBBt as our models. We characterize low-volume Differential Scanning Fluorimetry (nanoDSF), Isothermal Calorimetry (ITC), Hydrogen/Deuterium eXchange (HDX), X-ray crystallography (MX). The data indicate ligand pose away from hinge dominates entire tested range (5.5–8.5). insensitivity mode to attributed perturbation upon keeps it in pocket at all values. However, minor population ligand, detectable only HDX, shifts towards acidic conditions. Our findings demonstrate electrostatic (ionic) interactions predominate over bonding.