In Depth Analysis on the Binding Sites of Adamantane Derivatives in HCV (Hepatitis C Virus) p7 Channel Based on the NMR Structure

Abstract

BackgroundThe 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.ResultsThe 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.ConclusionsSome 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.

Adamantyl Isothiocyanates as Mutant p53 Rescuing Agents and Their Structure–Activity Relationships

“…These values satisfy Lipinski’s rule of five . Such lipophilicity is favorable for the transport of molecules through the cell membrane and for protein binding as observed previously for adamantane-containing drugs. , …”

“…29 Such lipophilicity is favorable for the transport of molecules through the cell membrane and for protein binding as observed previously for adamantane-containing drugs. 30,31 To determine the biological activity and the structural features important for the activity, we divided Ad-ITCs into four categories: (1) Ad-ITCs with different alkyl chain lengths connecting the adamantane to ITC (1, 2, 3, 5, 6), (2) Ad-ITCs with electron-releasing substituents, electron-withdrawing substituents, branched chains, double bonds, or heteroatoms in the alkyl chain (4,8,9,10,12), (3) the Ad-ITC with a benzene ring between adamantane and ITC (7), and (4) Ad-ITC 11 with electron-releasing alkyl substituents on adamantane. The proliferation of p53 R280K MDA-MB-231 TNBC cells treated with various concentrations of Ad-ITCs 1−12 or Ad-compound 13 for 24 or 72 h was compared with dimethyl sulfoxide (DMSO)-treated cells (as a control).…”

Microhydrated clusters of a pharmaceutical drug: infrared spectra and structures of amantadineH+(H2O)n

“…Under conditions of pharmaceutical action, AmaH + clearly occurs in its N-protonated form and the acidic protons of the NH 3 + group interact strongly with various bio-active molecular binding sites via H-bonding or cation–π interactions (docking). 112…”

“…Under conditions of pharmaceutical action, AmaH + clearly occurs in its N-protonated form and the acidic protons of the NH 3 + group interact strongly with various bio-active molecular binding sites via H-bonding or cation-p interactions (docking). 112 It is instructive to compare microhydration in AmaH + (I)(H 2 O) n with that in Ama + (I)(H 2 O) n radical cation clusters to evaluate the impact of the additional proton attached to the NH 2 group (NH 3 + / NH 2 + ) on the structure of the hydration shell as well as on the strength the NHÁ Á ÁO ionic H-bonds. Microhydration of AmaH + (I) shows the same preferential cluster growth as Ama + (I)(H 2 O) n , in which the N-H bonds are first hydrated and then a H 2 O solvent network is formed.…”

Cell culture-adaptive mutations in hepatitis C virus promote viral production by enhancing viral replication and release

“…As a small membrane polypeptide, the HCV p7 channel plays multiple roles in virus life cycle and mediates several biological functions in HCV infection[ 41 ]. The p7 consists of six equivalent hydrophobic pockets between the peripheral and pore-forming helices[ 42 ].…”