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

Yang, Yang; Xu, Zhijian; Zhang, Zhengyan; Yang, Zhuo; Liu, Yingtao; Wang, Jinan; Cai, Tingting; Li, Shujin; Chen, Kaixian; Shi, Jiye; Zhu, Weiliang

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

2015

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.

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