Assessment of enzyme inhibition : a review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs

Both authors are grateful for the collaborations on multi-target drugs facilitated by COST Action CM1103 (2011-2015).The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.Publisher PDFPeer reviewe

Dietary Phytochemicals as Inhibitors of Primary Amine Oxidase

Phytochemicals such as methylxanthines, catechins and polyphenols show health benefits in a range of diseases although their mechanism of action is not fully understood. Primary Amine Oxidase (PrAO) is widely recognised as a therapeutic drug target for the treatment of inflammatory, vascular and neurodegenerative diseases. Previous work in our laboratories showed that caffeine inhibited bovine PrAO activity with a Ki of 1.0mM. In the present study we examined a range of methylxanthines and catechins as inhibitors of bovine PrAO. The methylxanthines tested were caffeine, paraxanthine, theophylline, theobromine and 7-methylxanthine. Of these, only theobromine was an inhibitor with an IC50 of ca. 300µM. Calculations indicated that theobromine in foods could inhibit PrAO activity by 20%. The effect of dietary catechins; epicatechin, epicatechin gallate and epigallocatechingallate was even more significant with IC50 values in the micromolar region. However, inhibition by catechins was complicated by apparent activation of PrAO at high concentrations although this was not significant at physiologically attainable levels. Nonetheless, these findings indicate that a range of dietary phytochemicals could affect PrAO activity in vivo. We suggest that the health benefits associated with consumption of certain phytochemicals may be attributed to PrAO inhibition

Utjecaj korištenja probiotika i prebiotika na aromatske spojeve i teksturalna i senzorska svojstva simbiotskog kozjeg sira

The aim of this study was to evaluate the effects of probiotics as an adjunct culture, and the use of inulin and oligofructose as a prebiotic product, on symbiotic goat cheeses during their ripening period. The control group had the lowest value in terms of aromatic compounds, and the probiotics used in the production of cheese increased the aromatic substances. The control group was found to have the highest hardness values and that the use of prebiotics and probiotic cultures in cheese production significantly changed the textural profile depending on the probiotic and prebiotic type. The most favoured cheeses were found to contain E. faecium and oligofructose.U ovom radu istražen je utjecaj probiotika, te inulina i oligofruktoze, na simbiotski kozji sir tijekom zrenja. U kontrolnoj grupi su utvrđene najniže koncentracije aromatskih spojeva, dok je dodatak probiotika u proizvodnji sira povećao koncentraciju aromatskih spojeva. Također, u sirevima iz kontrolne grupe su utvrđene najveće vrijednosti čvrstoće. Dodatak probiotika i prebiotika je signifikantno utjecao na teksturalne karakteristike sira. Sirevi koji su ocjenjeni kao najbolji, proizvedeni su uz dodatak E. facium i oligofruktoze

GlycoForm and Glycologue: two software applications for the rapid construction and display of N-glycans from mammalian sources

<p>Abstract</p> <p>Background</p> <p>The display of <it>N</it>-glycan carbohydrate structures is an essential part of glycoinformatics. Several tools exist for building such structures graphically, by selecting from a palette of symbols or sugar names, or else by specifying a structure in one of the chemical naming schemes currently available.</p> <p>Findings</p> <p>In the present work we present two tools for displaying <it>N</it>-glycans found in the mammalian CHO (Chinese hamster ovary) cell line, both of which take as input a 9-digit identifier that uniquely defines each structure. The first of these, GlycoForm, is designed to display a single structure automatically from an identifier entered by the user. The display is updated in real time, using symbols for the sugar residues, or in text-only form. Structures can be added to a library, which is recorded in a preference file and loaded automatically at start. Individual structures can be saved in a variety of bitmap image formats. The second program, Glycologue, reads a file containing columnar data of nine-digit codes, which can be displayed on-screen and printed at high resolution.</p> <p>Conclusion</p> <p>A key advantage of both programs is the speed and facility with which carbohydrate structures can be drawn. It is anticipated that these programs will be useful to glycobiologists, systems biologists and biotechnologists interested in <it>N</it>-glycosylation systems in mammalian cells.</p