Small molecule ligand docking to genotype specific bundle structures of hepatitis C virus (HCV) p7 protein.
The genome of hepatitis C virus encodes for an essential 63 amino acid polytopic protein p7 of most likely two transmembrane domains (TMDs). The protein is identified to self-assemble thereby rendering lipid membranes permeable to ions. A series of small molecules such as adamantanes, imino sugars and guanidinium compounds are known to interact with p7. A set of 9 of these small molecules is docked against hexameric bundles of genotypes 5a (bundle-5a) and 1b (bundle-1b) using LeadIT. Putative sites for bundle-5a are identified within the pore and at pockets on the outside of the bundle. For bundle-1b preferred sites are found at the site of the loops. Binding energies are in favour of the guanidinium compounds. Rescoring of the identified poses with HYDE reveals a dehydration penalty for the guanidinium compounds, leaving the adamantanes and imino sugar in a better position. Binding energies calculated by HYDE and those by LeadIT indicate that all compounds are moderate binders.
Institute of Biophotonics, School of Biomedical Science and Engineering, and Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei 112, Taiwan.
Niklas
N
Laasch
Institute of Biophotonics, School of Biomedical Science and Engineering, and Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei 112, Taiwan.
Monoj Mon
MM
Kalita
Institute of Biophotonics, School of Biomedical Science and Engineering, and Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei 112, Taiwan.
Stephen
S
Griffin
Institute of Biophotonics, School of Biomedical Science and Engineering, and Biophotonics & Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei 112, Taiwan. Electronic address: wfischer@ym.edu.tw.
Wolfgang B
WB
Fischer
D000595:Amino Acid Sequence; D001665:Binding Sites; D008024:Ligands; D054852:Small Molecule Libraries / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D000086082:Viroporin Proteins
D008024:Ligands; D054852:Small Molecule Libraries; D014764:Viral Proteins; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins
Adamantanes; Antivirals; Docking approach; Guanidinium compounds; Imino sugars; MD simulations; p7 of HCV