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

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 repu...