ABSTRACT
In the last years, molecular docking emerged as a powerful tool to investigate the interactions between opioid ligands and their receptors, thus driving the design and development of new selective agonists or antagonists of therapeutic interest. This review especially covers the most representative and recent comparative molecular docking analyses of structurally related compounds, as well as of agonists and antagonists within the active and inactive states of the receptors. The comparative analyses gave important information on the structural determinants responsible for the affinity and selectivity of the ligands, and defined the features responsible for the activation of the receptors. A special section is dedicated to the analyses of recently discovered, unusual agonists lacking of the tyramine pharmacophore, such as Salvinorin A, and the cyclopeptides which comprise the D-Trp-Phe pharmacophoric motif. For the atypical structure of these compounds, the docking proved to be essential to disclose how they interact with and activate the receptors.
Subject(s)
Analgesics, Opioid/chemistry , Drug Design , Narcotic Antagonists , Opioid Peptides/chemistry , Receptors, Opioid/agonists , Animals , Humans , Receptors, Opioid/chemistryABSTRACT
AIMS: This short review aims at summarizing the current information on Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) structure and function focusing also on the therapeutic possibilities based on the inhibition of this protein. DATA SYNTHESIS: PCSK9 has been recently discovered as the third gene involved in autosomal dominant hypercholesterolemia. PCSK9 binds and favors degradation of the low-density lipoprotein receptor (LDLR) and thereby modulates the plasma levels of LDL-cholesterol (LDL-C). Some of the natural occurring PCSK9 mutations increase the protein function (gain of function) and cause hypercholesterolemia, whereas loss of function mutations associate with hypocholesterolemia. Since the loss of a functional PCSK9 in humans is not associated with apparent deleterious effects, this protease is an attractive target for the development of lowering plasma LDL-C agents, either alone or in combination with statins. CONCLUSION: Inhibition of PCSK9 is emerging as a novel strategy for the treatment of hypercholesterolemia and data obtained from pre-clinical studies show that use of monoclonal antibodies, antisense oligonucleotides and short interfering RNA are effective in reducing LDL-C, clinical studies, accompanied by a better understanding of PCSK9 biology, are now necessary to address whether these new compounds will have a future in clinical practice.
Subject(s)
Hypercholesterolemia/drug therapy , Serine Endopeptidases/chemistry , Serine Endopeptidases/physiology , Serine Proteinase Inhibitors/therapeutic use , Animals , Cholesterol, LDL/blood , Humans , Hypercholesterolemia/genetics , Hypolipidemic Agents , Mutation , Proprotein Convertase 9 , Proprotein Convertases , Receptors, LDL/metabolism , Serine Endopeptidases/genetics , Structure-Activity RelationshipABSTRACT
The antioxidant constituents of essential oils (EOs) of Rosmarinus officinalis L. (α-pinene chemotype) were isolated at the flowering (A), post-flowering (B), and vegetative stages (C). GC-MS was used to analyze total chemical composition, Folin-Ciocalteau and Prussian blue methods for reducing substances. Radical scavenging capacity (DPPH test, IC(50) 36.78±0.38, 79.69±1.54, 111.94±2.56µL) and anti-lipoperoxidant activity (TBARS, IC(50) 0.42±0.04, 1.20±0.06µL, 4.07±0.05µL) differed widely in the three stages. Antioxidant activity, identified after silica gel fractionation chromatography, was closely related (R(2)=0.9959) to each EO's content of hydroxilated derivatives, (containing alcohols, phenols and 1,8 cineole): 15.26±0.12%, 7.22±0.06%, and 5.09±0.10% in EOs from A, B, and C. Modeling the C, H, O terpenes in a simulated phospholipid bilayer indicated that anti-lipoperoxidant activity depended on the stability and rapidity of their interactions with the membrane bilayer components, and their positioning over its surface.
Subject(s)
Antioxidants/analysis , Gas Chromatography-Mass Spectrometry/methods , Rosmarinus/metabolism , Animals , Antioxidants/chemistry , Biphenyl Compounds/chemistry , Chromatography, Gel/methods , Ferrocyanides/chemistry , Gels/chemistry , Indicators and Reagents/chemistry , Inhibitory Concentration 50 , Male , Oils, Volatile , Peroxides/chemistry , Picrates/chemistry , Plant Extracts/chemistry , Rats , Rats, Wistar , Silicon Dioxide/chemistry , Spectrophotometry/methodsABSTRACT
The crystallographic structure of an engineered flavodoxin mutant from Desulfovibrio vulgaris has been analysed. Site-directed mutagenesis was used to substitute serine 35 with a cysteine to provide a possible covalent linkage. The crystal structure of the semiquinone form of this mutant is similar to the corresponding oxidation state of the wild-type flavodoxin. Analysis of the structural changes reveals the interaction between N(5)H of the flavin and the carbonyl O atom of Gly61 to be critical for modulation of the electrochemical properties of the protein.
Subject(s)
Desulfovibrio desulfuricans/genetics , Flavodoxin/chemistry , Flavodoxin/genetics , Amino Acid Substitution , Benzoquinones/chemistry , Crystallography, X-Ray , Desulfovibrio desulfuricans/chemistry , Models, Molecular , Spectrophotometry, UltravioletABSTRACT
The structural characteristics of an immunostimulating agent (3-(5-thioxo-L-prolyl)-L-thiazolidine-4-carboxylic acid) have been established using a combination of 1H and 13C NMR spectroscopy, molecular mechanic calculations (in vacuo and in solution) and X-ray crystallographic analyses. Conformational calculations and NMR spectra identify two classes of conformers, cis and trans, around the peptide bond between the rings, while in the solid state only the cis form has been found.
