ABSTRACT
The group of 19 thiosemicarbazones (TSCs) were synthesized and its inhibitory activity toward mushroom tyrosinase and ability to inhibition of melanogenesis in B16 cells were investigated. Moreover, molecular docking of these compounds to the active site of the enzyme was performed. The obtained results allowed to make the structure-activity relationship (SAR) analysis. Kinetic studies revealed that TSCs 1, 2, 11 and 18 have better inhibitory properties than kojic acid, a reference compound, with the best inhibitory constant (Ki) value of 0.38⯵M for TSC 2. According to SAR analysis, the smaller and less branched molecules exhibit higher affinity to the enzyme. Melanin production in B16 cells was inhibited by all investigated compounds at micromolar level. Most of compounds studied in this work can be considered as potent inhibitors of tyrosinase and melanogenesis. They may have broad application in food preservatives and cosmetics. Combined results of molecular docking and SAR analysis can be helpful in designing novel tyrosinase inhibitors of desired properties.
Subject(s)
Agaricales/enzymology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Melanins/antagonists & inhibitors , Monophenol Monooxygenase/antagonists & inhibitors , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacology , Agaricus/enzymology , Animals , Biosynthetic Pathways/drug effects , Cell Line, Tumor , Melanins/metabolism , Mice , Molecular Docking Simulation , Monophenol Monooxygenase/metabolismABSTRACT
The increasing interest in peptidomimetics of biological relevance prompted us to synthesize a series of cyclic peptides comprising trans-2-aminocyclohexane carboxylic acid (Achc) or trans-2-aminocyclopentane carboxylic acid (Acpc). NMR experiments in combination with MD calculations were performed to investigate the three-dimensional structure of the cyclic peptides. These data were compared to the conformational information obtained by electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopy. Experimental VCD spectra were compared to theoretical VCD spectra computed quantum chemically at B3LYP/6-31G(d) density functional theory (DFT) level. The good agreement between the structural features derived from the VCD spectra and the NMR-based structures underlines the applicability of VCD in studying the conformation of small cyclic peptides.
Subject(s)
Cyclohexanecarboxylic Acids/chemistry , Cyclohexylamines/chemistry , Peptides, Cyclic/chemistry , Circular Dichroism/methods , Cycloleucine/analogs & derivatives , Cycloleucine/chemistry , Molecular Conformation , Molecular Dynamics Simulation , Nuclear Magnetic Resonance, Biomolecular , PeptidomimeticsABSTRACT
Synthesis, structural and biological studies of pentapeptides containing two DeltaPhe residues (Z and E isomers) in position 2 and 4 in peptide chain were performed. All the investigated peptides adopted bent conformation and majority of them could exist as two different conformers in solution. Only pentapeptides, containing free N-termini appeared to act as weak inhibitors of cathepsin C with the slow-binding, competitive mechanism of inhibition, free acids being bound slightly better than their methyl esters. Results of molecular modeling suggested significant difference between peptides, depending of the type of amino acid residue in position 5 in peptide chain. Dehydropeptides containing Gly residue in this position may act as competitive slow-reacting substrates and therefore exhibit inhibitory-like properties.
