Halogen bonding at the ATP binding site of protein kinases: Preferred geometry and topology of ligand binding

Abstract

Halogenated ligands have been widely developed as potent, and frequently selective, inhibitors of protein kinases (PK). Herein, all structures of protein kinases complexed with a halogenated ligand, identified in the PDB, were analyzed in the context of eventual contribution of halogen bonding to protein-ligand interactions. Global inspection shows that two carbonyl groups of residues located in the hinge region are the most abundant halogen bond acceptors. In contrast to solution data, well-defined water molecules, located at sites conserved across most PK structures, are also involved in halogen bonding. Analysis of cumulative distributions of halogen-acceptor distances shows that structures displaying short contacts involving a halogen atom are overpopulated, contributing together to clearly defined maxima of 2.82, 2.91 and 2.94 Å for chlorine, bromine and iodine, respectively. The angular preference of a halogen bond favors ideal topology (180°, 120°) for iodine. For bromine the distribution is much more dispersed, and no such preference was found for chlorine.

Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib

“…In addition to the role of water, recently, the role of halogen atoms (F, C, Br and I; several drug candidates are halogenated including 20% of ligands in the pdb 27 ) in contributing to affinity and selectivity through “halogen bonds” 28–30 is being recognized, both through direct contacts with the KD and through buried water 31 . Since both gefitinib and afatinib are halogenated, we carried out detailed analyses of water mediated hydrogen bonds and halogen bond interactions.…”

A Protein Data Bank Survey Reveals Shortening of Intermolecular Hydrogen Bonds in Ligand-Protein Complexes When a Halogenated Ligand Is an H-Bond Donor

“…Currently, halogenated compounds are widely used in screening libraries, and comprise almost 20% of low-mass protein ligands listed in the Protein Data Bank (PDB). The role of halogenated ligands in biological systems has been widely reviewed, amongst others, by Auffinger et al [18], Parisini et al [24], Rendine et al , Voth & Ho [25], Voth et al [26], Wilcken et al [27] and Poznański & Shugar [28].…”

Could Quantum Mechanical Properties Be Reflected on Classical Molecular Dynamics? The Case of Halogenated Organic Compounds of Biological Interest

“…Despite the great effort being made by scientific programmers to enhance the quality of classical molecular simulation techniques, much more can be done by the user to improve interand intramolecular interactions outcomes. It should be kept in mind that intramolecular interactions are the driving force of most biomolecular phenomena (Martins et al, 2003;Adesokan et al, 2004;Ramalho et al, 2009;Poater et al, 2011;Ben-Naim, 2012;Hongo et al, 2013;Poznanski and Shugar, 2013). They are known to be quantum chemical phenomena that go beyond the classical description of matter and, in particular cases, they cannot be understood by simple electrostatic or dispersion schemes (Ramalho and da Cunha, 2011;Esrafili and Ahmadi, 2012;Wolters et al, 2014).…”