Inhibition Of Multiple Enzymes Research Articles

Sesquiterpenoids from Alpinia oxyphylla with GLP-1 Stimulative Effects through Ca2+/CaMKII and PKA Pathways and Multiple-Enzyme Inhibition.

Six new sesquiterpenoids (1-6), a pair of enantiomers (7a and 7b), and six known ones (8-13) were isolated from the fruits of Alpinia oxyphylla. The structures of the new compounds were elucidated by extensive spectroscopic data and ECD calculations. The stereochemistry of 7a and 7b was reported for the first time. All compounds showed significant GLP-1 stimulation in NCI-H716 cells with promoting ratios ranging from 90.4 to 668.9% at 50 μM. Mechanism study indicated that compound 6 stimulated GLP-1 secretion mainly by regulating the transcription and the shearing process of proglucagon, while compound 13 exerted its effects through up-regulating prkaca levels. Interestingly, the GLP-1 stimulative effects of 6 and 13 were both closely related with Ca2+/CaMKII and PKA pathways but irrelevant to TGR5 and GPR119 receptors. Moreover, most compounds exhibited inhibitory activity against α-glucosidase and PTP1B at concentrations of 100 and 200 μM, while showing no activity against GPa. Compounds 3, 9, 11, and 13 could suppress α-glucosidase with IC50 values of 190.0, 204.0, 181.8, and 159.6 μM, equivalent to acarbose (IC50 = 212.0 μM). This study manifests that A. oxyphylla contains diverse sesquiterpenoids with multiple activities.

Coumarin-Chalcone Hybrids as Inhibitors of MAO-B: Biological Activity and In Silico Studies.

Fourteen coumarin-derived compounds modified at the C3 carbon of coumarin with an α,β-unsaturated ketone were synthesized. These compounds may be designated as chalcocoumarins (3-cinnamoyl-2H-chromen-2-ones). Both chalcones and coumarins are recognized scaffolds in medicinal chemistry, showing diverse biological and pharmacological properties among which neuroprotective activities and multiple enzyme inhibition, including mitochondrial enzyme systems, stand out. The evaluation of monoamine oxidase B (MAO-B) inhibitors has aroused considerable interest as therapeutic agents for neurodegenerative diseases such as Parkinson’s. Of the fourteen chalcocumarins evaluated here against MAO-B, ChC4 showed the strongest activity in vitro, with IC50 = 0.76 ± 0.08 µM. Computational docking, molecular dynamics and MM/GBSA studies, confirm that ChC4 binds very stably to the active rMAO-B site, explaining the experimental inhibition data.

Immunomodulatory and Anti-Inflammatory Effects of Fucoidan: A Review.

Inflammation is the initial response of the immune system to potentially harmful stimuli (e.g., injury, stress, and infections). The process involves activation of macrophages and neutrophils, which produce mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), pro-inflammatory and anti-inflammatory cytokines. The pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) are considered as biomarkers of inflammation. Even though it occurs as a physiological defense mechanism, its involvement in the pathogenesis of various diseases is reported. Rheumatoid arthritis, inflammatory bowel disease, Alzheimer’s disease, and cardiovascular diseases are only a part of the diseases, in which pathogenesis the chronic inflammation is involved. Fucoidans are complex polysaccharides from brown seaweeds and some marine invertebrates, composed mainly of l-fucose and sulfate ester groups and minor amounts of neutral monosaccharides and uronic acids. Algae-derived fucoidans are studied intensively during the last years regarding their multiple biological activities and possible therapeutic potential. However, the source, species, molecular weight, composition, and structure of the polysaccharides, as well as the route of administration of fucoidans, could be crucial for their effects. Fucoidan is reported to act on different stages of the inflammatory process: (i) blocking of lymphocyte adhesion and invasion, (ii) inhibition of multiple enzymes, and (iii) induction of apoptosis. In this review, we focused on the immunemodulating and anti-inflammatory effects of fucoidans derived from macroalgae and the models used for their evaluation. Additional insights on the molecular structure of the compound are included.

Plasmodium Drug Targets Outside the Genetic Control of the Parasite

Drug development often seeks to find "magic bullets" which target microbiologic proteins while not affecting host proteins. Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are "magic shotguns" which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8- aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials. Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins or unchangeable cellular targets will slow the pace of drug resistance acquisition.

Multiple enzyme inhibition potential of Butea superba for management of erectile dysfunction

Multiple enzyme inhibition potential of Butea superba for management of erectile dysfunction

Quantifying and Predicting the Promiscuity and Isoform Specificity of Small-Molecule Cytochrome P450 Inhibitors

Drug promiscuity (i.e., inhibition of multiple enzymes by a single compound) is increasingly recognized as an important pharmacological consideration in the drug development process. However, systematic studies of functional or physicochemical characteristics that correlate with drug promiscuity are handicapped by the lack of a good way of quantifying promiscuity. In this article, we present a new entropy-based index of drug promiscuity. We apply this index to two high-throughput data sets describing inhibition of cytochrome P450 isoforms by small-molecule drugs and drug candidates, and we demonstrate how drug promiscuity or specificity can be quantified. For these drug-metabolizing enzymes, we find that there is essentially no correlation between a drug's potency and specificity. We also present an index to quantify the susceptibilities of different enzymes to inhibition by diverse substrates. Finally, we use partial least-squares regression to successfully predict isoform specificity and promiscuity of small molecules, using a set of fingerprint-based descriptors.

Inhibition of aromatic L-amino acid decarboxylase and tyrosine aminotransferase by the monoamine oxidase inhibitor phenelzine.

The concentration of p-tyramine in the rat striatum was increased significantly by intraperitoneal injection of phenelzine (5 or 100 mg/kg). Unlike other monoamine oxidase (MAO) inhibitors, phenelzine had no effect on p-tyramine levels in the first 1-2 h following injection. The high dose of phenelzine increased the p-tyramine levels much more than the low dose. In addition, the high dose of phenelzine increased striatal p-tyrosine levels significantly 12 h after injection. Further studies showed that phenelzine inhibited the tyrosine aminotransferase activity of rat liver homogenates; the IC50 was 50 microM. Phenelzine also inhibited the aromatic L-amino acid decarboxylase activity of rat brain homogenate with an IC50 of 25 microM. Following intraperitoneal injection of 100 mg/kg phenelzine, the initial concentration of phenelzine in the striatum appears to be high enough to inhibit aromatic L-amino acid decarboxylase. It is suggested that the multiple enzyme inhibition caused by administration of high doses of phenelzine accounts for its unusual effects on striatal p-tyramine levels compared with other MAO inhibitors, i.e., its initial lack of effect on p-tyramine levels followed later by very large increases in p-tyramine levels.