In depth analysis on the binding sites of adamantane derivatives in HCV (hepatitis C virus) p7 channel based on the NMR structure.
BACKGROUND
The recently solved solution structure of HCV (hepatitis C virus) p7 ion channel provides a solid structure basis for drug design against HCV infection. In the p7 channel the ligand amantadine (or rimantadine) was determined in a hydrophobic pocket. However the pharmocophore (-NH2) of the ligand was not assigned a specific binding site.


RESULTS
The possible binding sites for amino group of adamantane derivatives is studied based on the NMR structure of p7 channel using QM calculation and molecular modeling. In the hydrophobic cavity and nearby three possible binding sites are proposed: His17, Phe20, and Trp21. The ligand binding energies at the three binding sites are studied using high level QM method CCSD(T)/6-311+G(d,p) and AutoDock calculations, and the interaction details are analyzed. The potential application of the binding sites for rational inhibitor design are discussed.


CONCLUSIONS
Some useful viewpoints are concluded as follows. (1) The amino group (-NH2) of adamantane derivatives is protonated (-NH3+), and the positively charged cation may form cation-π interactions with aromatic amino acids. (2) The aromatic amino acids (His17, Phe20, and Trp21) are the possible binding sites for the protonated amino group (-NH3+) of adamantane derivatives, and the cation-π bond energies are 3 to 5 times stronger than the energies of common hydrogen bonds. (3) The higher inhibition potent of rimantadine than amantadine probably because of its higher pKa value (pKa = 10.40) and the higher positive charge in the amino group. The potential application of p7 channel structure for inhibitor design is discussed.
State Key Laboratory of Non-food Biomass and Enzyme Technology, National Engineering Research Center for Non-food Biorefinery, Guangxi Academy of Sciences, Nanning, Guangxi, China; Gordon Life Science Institute, San Diego, California, United States of America.
Qi-Shi
QS
Du
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China.
Shu-Qing
SQ
Wang
State Key Laboratory of Non-food Biomass and Enzyme Technology, National Engineering Research Center for Non-food Biorefinery, Guangxi Academy of Sciences, Nanning, Guangxi, China; Life Science and Biotechnology College, Guangxi University, Nanning, Guangxi, China.
Dong
D
Chen
Life Science and Biotechnology College, Guangxi University, Nanning, Guangxi, China.
Jian-Zong
JZ
Meng
State Key Laboratory of Non-food Biomass and Enzyme Technology, National Engineering Research Center for Non-food Biorefinery, Guangxi Academy of Sciences, Nanning, Guangxi, China; Life Science and Biotechnology College, Guangxi University, Nanning, Guangxi, China.
Ri-Bo
RB
Huang
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D055808:Drug Discovery; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*
D000998:Antiviral Agents; D007473:Ion Channels; D014764:Viral Proteins; D000218:Adamantane