title: Structure-based design of inhibitors of NS3 serine protease of hepatitis C virus.
abstract: We have designed small focused combinatorial library of hexapeptide inhibitors of NS3 serine protease of the hepatitis C virus (HCV) by structure-based molecular design complemented by combinatorial optimisation of the individual residues. Rational residue substitutions were guided by the structure and properties of the binding pockets of the enzyme's active site. The inhibitors were derived from peptides known to inhibit the NS3 serine protease by using unusual amino acids and alpha-ketocysteine or difluoroaminobutyric acid, which are known to bind to the S1 pocket of the catalytic site. Inhibition constants (Ki) of the designed library of inhibitors were predicted from a QSAR model that correlated experimental Ki of known peptidic inhibitors of NS3 with the enthalpies of enzyme-inhibitor interaction computed via molecular mechanics and the solvent effect contribution to the binding affinity derived from the continuum model of solvation. The library of the optimised inhibitors contains promising drug candidates-water-soluble anionic hexapeptides with predicted Ki* in the picomolar range.
authors: International Centre for Science and High Technology, UNIDO, AREA Science Park, Padriciano 99, I-34012, Trieste, Italy.
authors: Vladimír
authors: V
authors: Frecer
authors: Martin
authors: M
authors: Kabelác
authors: Piergiuseppe
authors: P
authors: De Nardi
authors: Sabrina
authors: S
authors: Pricl
authors: Stanislav
authors: S
authors: Miertus
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D019151:Peptide Library; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D012997:Solvents; D013816:Thermodynamics
chemical_list: D019151:Peptide Library; D015842:Serine Proteinase Inhibitors; D012997:Solvents; D012697:Serine Endopeptidases