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 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.
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Yang
Y
Yang
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|State Key Laboratory of Medicinal Chemical Biology, Nankai University , 94 Weijin Road, Nankai District, Tianjin300071, China.
Zhijian
Z
Xu
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|College of Chemistry, Chemical Engineering and Materials Science of Soochow University, Soochow University , Suzhou, Jiangsu 215123, China.
Zhengyan
Z
Zhang
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Zhuo
Z
Yang
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Yingtao
Y
Liu
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Jinan
J
Wang
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Tingting
T
Cai
College of Chemistry, Chemical Engineering and Materials Science of Soochow University, Soochow University , Suzhou, Jiangsu 215123, China.
Shujin
S
Li
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Kaixian
K
Chen
Informatics Department, UCB Pharma , 216 Bath Road, Slough SL1 4EN, United Kingdom.
Jiye
J
Shi
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
Weiliang
W
Zhu
D001120:Arginine / Q000378:metabolism; D030562:Databases, Protein; D015195:Drug Design; D004583:Electrons; D019791:Guanidine / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D008024:Ligands; D011506:Proteins; D001120:Arginine; D019791:Guanidine