文摘
A database survey in this study revealed for the first time that there are 227 counterintuitive like-charge guanidinium pairings (Gdm+鈥揂rg pairings) between ligands and receptors in the Protein Data Bank, implying the potential guanidinium鈥揳rginine 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+鈥揂rg pairing improved the potency of the drug by more than 8-fold in a typical case. On the basis of the survey, six ligand鈥損rotein complexes with typical Gdm+鈥揂rg 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 鈭?.0 to 鈭?.5 kcal/mol in DMSO and water, comparable to common intermolecular interactions. The calculations also unveiled that the Gdm+鈥揂rg 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+鈥揂rg 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.