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

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• 作者：Yang Yang ; Zhijian Xu ; Zhengyan Zhang ; Zhuo Yang ; Yingtao Liu ; Jinan Wang ; Tingting Cai ; Shujin Li ; Kaixian Chen ; Jiye Shi ; Weiliang Zhu
• 刊名：Journal of Physical Chemistry B
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：119
• 期：36
• 页码：11988-11997
• 全文大小：534K
• ISSN：1520-5207

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.