Structure-based design of inhibitors of NS3 serine protease of hepatitis C virus
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 enzymes active site. The inhibitors were derived from peptides known to inhibit the NS3 serine protease by using unusual amino acids and ?-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 enzymeinhibitor 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 candidateswater-soluble anionic hexapeptides with predicted in the picomolar range.
ac acetyl asa ?-carboxyaspartic acid tbu tert-butylglycine cha ?-cyclohexylalanine cyo ?-ketocysteine dif ? ?-diphenylalanine fab ? ?-difluoro-?-amino-?-ketopentanoic acid gla ?-carboxyglutamic acid glr glutaric acid cpa ?-carboxypropionylalanine nal ?-napthylalanine nap napthylglycin nva norvaline phg ?-phenylglycine suc succinic acid tro 7-hydroxytryptofan trc 4-carboxytryptofan hcv hepatitis c virus ns3 viral non-structural protein number 3 of hcv ns4a viral non-structural protein number 4 of hcv cofactor of the ns3 ns3/4a complex of ns3 with cofactor ns4a mm molecular mechanics qsar quantitative structureactivity relationships ki inhibition constant logpo/w log of partitioning coefficient in octanol/water system.