Like-Charge Guanidinium Pairing between Ligand and Receptor: An Unusual Interaction for Drug Discovery and Design?

Abstract

A database survey in this study revealed for the first time that there are 227 counterintuitive like-charge guanidinium pairings (Gdm(+)-Arg pairings) between ligands and receptors in the Protein Data Bank, implying the potential guanidinium-arginine binding between guanidine-containing drugs and their target proteins. Furthermore, there are 145 guanidine-containing molecules in the DrugBank, showing the prevalence of guanidinium groups in drugs. It has also been reported that the introduction of a guanidinium group forming Gdm(+)-Arg pairing improved the potency of the drug by more than 8-fold in a typical case. On the basis of the survey, six ligand-protein complexes with typical Gdm(+)-Arg pairings were chosen for QM/MM calculations. The calculations at the B97-D/6-311++g(d,p) level revealed that the interaction could be as strong as -1.0 to -2.5 kcal/mol in DMSO and water, comparable to common intermolecular interactions. The calculations also unveiled that the Gdm(+)-Arg pairing interactions change from repulsive to attractive with the increase of dielectric constant, suggesting that the dielectric constant has a general stabilization effect on the Gdm(+)-Arg pairing. This study suggested that the like-charge guanidinium pairing interaction could be used not only for tuning the physical and chemical properties of drug leads but also for improving ligand binding affinity.

On the Stability of Interactions between Pairs of Anions – Complexes of MCl3− (M=Be, Mg, Ca, Sr, Ba) with Pyridine and CN−

“…confirmed this finding in other systems and defined an electrostatic attraction region in terms of electric field lines. They found that immersion of these complexes in a polarizable medium stabilized them to the point where they became stable relative to the isolated subunits, confirmed by a later analysis of guanidinium pairings . The catalogue of metastable H‐bonded complexes of like charged ions was expanded to dications and dianions.…”

“…Examination of ionic liquids provides a number of examples. Cationic guanidinium side chains, for example, can associate with one another in poly‐Arg within aqueous or protein environments . With regard to gas phase systems without recourse to a surrounding polarizable medium to disperse the charges, Weinhold and Klein identified a number of such ion pairs, both cationic and anionic, dubbing them anti‐electrostatic H‐bonds.…”

“…Considering this background, it was quite surprising when a number of reports appeared asserting that a H‐bond could be present between a pair of species of like charge . One would have presumed that the Coulombic repulsion ought to prevent the two ions from approaching one another.…”

Arginine “Magic”: Guanidinium Like-Charge Ion Pairing from Aqueous Salts to Cell Penetrating Peptides

“…32,[38][39][40] Also, the unusually large number of ligands containing Gdm + groups interacting with Arg amino acids in receptors indicates a potential importance of the like-charge pairing in drug design as well. 41 At the same time, Gdm + ion pairing has also been demonstrated by a combination of capillary electrophoresis and MD simulations. Namely, in electrophoresis experiments it has been observed that addition of GdmCl to the solution of tetraarginine (Arg4) leads to an increased mobility of Arg4, while upon addition of NaCl no mobility enhancement has been observed ( Table 1).…”

ONIOM and FMO‐EDA study of metabotropic glutamate receptor 1: Quantum insights into the allosteric binding site

“…QM/MM methods are especially suitable for studying large biological systems and, to date, have provided molecular‐level insights into many processes, such as the photosensitivity of visual pigments, enzyme catalysis, drug recognition by receptors, and cytotoxic activity mechanisms . It must be stressed that relatively few ONIOM studies have focused on one of the most important groups of biological targets, a family of G protein‐coupled receptors (GPCRs).…”