Small molecule ligand docking to genotype specific bundle structures of hepatitis C virus (HCV) p7 protein

• Binding poses of antivirals to hexameric bundles of p7 of HCV genotype 5a and 1b.
• LeadIT suggests guanidinium compounds then imino sugars, adamantanes.
• Rescoring with HYDE reverses the order.
• Favored binding sites within the pore and at outside pockets for bundle-5a.
• Favored binding sites at the sites of the loops for bundle-1b.

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.

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