Investigation of the slow inhibition of almond β-glucosidase and yeast isomaltase by 1-azasugar inhibitors: evidence for the ‘direct binding’ model

2000 ◽  
Vol 349 (1) ◽  
pp. 211-215 ◽  
Author(s):  
Anders LOHSE ◽  
Tore HARDLEI ◽  
Astrid JENSEN ◽  
Igor W. PLESNER ◽  
Mikael BOLS
Keyword(s):  
Rate Constants ◽  
Binding Model ◽  
Progress Curve ◽  
Dependent Inhibition ◽  
Direct Binding ◽  
Glycosidase Inhibitor ◽  
The Difference ◽  
Identical Rate ◽  
Time Dependent Inhibition ◽  
Slow Dissociation

(-)-1-Azafagomine [(3R,4R,5R)-4,5-dihydroxy-3-hydroxymethylhexahydropyridazine; inhibitor 1] is a potent glycosidase inhibitor designed to mimic the transition state of a substrate undergoing glycoside cleavage. The inhibition of glycosidases by inhbitor 1 and analogues has been found to be a relatively slow process. This ‘slow inhibition’ process was investigated in the inhibition of almond β-glucosidase and yeast isomaltase by inhibitor 1 and analogues. Progress-curve experiments established that the time-dependent inhibition of both enzymes by inhibitor 1 was a consequence of relatively slow dissociation and association of the inhibitor from and to the enzyme, and not a result of slow interchanges between protein conformations. A number of hydrazine-containing analogues of inhibitor 1 also inhibited β-glucosidase and isomaltase slowly, while the amine isofagomine [(3R,4R,5R)-3,4-dihydroxy-5-hydroxymethylpiperidine; inhibitor 5] only inhibited β-glucosidase slowly. Inhibitor 1 and related inhibitors were found to leave almond β-glucosidase with almost identical rate constants, so that the difference in Ki values depended almost entirely on changes in the binding rate constant, kon. The same trend was observed for the inhibition of yeast isomaltase by inhibitor 1 and a related inhibitor. The values of the rate constants were obtained at 25 °C and at pH 6.8.

scholarly journals Time-dependent inhibition of PHD2

2017 ◽  
Vol 37 (3) ◽  
Author(s):  
Isabelle Tcholakov ◽  
Charles E. Grimshaw ◽  
Lihong Shi ◽  
Andre Kiryanov ◽  
Sean T. Murphy ◽  
...  
Keyword(s):  
Active Site ◽  
Dissociation Rate ◽  
Time Dependent ◽  
Hypoxic Stress ◽  
Hypoxia Inducible Factors ◽  
Prolyl Hydroxylases ◽  
Enzyme Active Site ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition ◽  
Slow Dissociation

Prolyl hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues that trigger the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. The present study provides a detail kinetic analysis for some of these inhibitors. The data generated in the present study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time.

Progress Curve Mechanistic Modeling Approach for Assessing Time-Dependent Inhibition of CYP3A4

2012 ◽  
Vol 40 (9) ◽  
pp. 1658-1667 ◽  
Author(s):  
Howard J. Burt ◽  
Henry Pertinez ◽  
Carolina Säll ◽  
Claire Collins ◽  
Ruth Hyland ◽  
...  
Keyword(s):  
Mechanistic Modeling ◽  
Time Dependent ◽  
Modeling Approach ◽  
Progress Curve ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition

scholarly journals 4-Phenethyl-1-Propargylpiperidine-Derived Dual Inhibitors of Butyrylcholinesterase and Monoamine Oxidase B

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4118
Author(s):  
Tjaša Mazej ◽  
Damijan Knez ◽  
Anže Meden ◽  
Stanislav Gobec ◽  
Matej Sova
Keyword(s):  
Monoamine Oxidase ◽  
Docking Studies ◽  
Monoamine Oxidase B ◽  
Mao B ◽  
Initial Expectation ◽  
Excellent Starting Point ◽  
Starting Point ◽  
Dependent Inhibition ◽  
Dual Inhibitors ◽  
Time Dependent Inhibition

The multi-target-directed ligands (MTDLs) strategy is encouraged for the development of novel modulators targeting multiple pathways in the neurodegenerative cascade typical for Alzheimer’s disease (AD). Based on the structure of an in-house irreversible monoamine oxidase B (MAO-B) inhibitor, we aimed to introduce a carbamate moiety on the aromatic ring to impart cholinesterase (ChE) inhibition, and to furnish multifunctional ligands targeting two enzymes that are intricately involved in AD pathobiology. In this study, we synthesized three dual hMAO-B/hBChE inhibitors 13–15, with compound 15 exhibiting balanced, low micromolar inhibition of hMAO-B (IC50 of 4.3 µM) and hBChE (IC50 of 8.5 µM). The docking studies and time-dependent inhibition of hBChE confirmed the initial expectation that the introduced carbamate moiety is responsible for covalent inhibition. Therefore, dual-acting compound 15 represents an excellent starting point for further optimization of balanced MTDLs.

Chromogenic Peptide Substrate Assays for Plasma Inhibitors of Plasma Kallikrein: Identification of the Major Inhibitors

1979 ◽  
Author(s):  
M.J. Gallimore ◽  
E. Amundsen ◽  
M. Larsbraaten ◽  
K. Lyngaas ◽  
E. Fareid
Keyword(s):  
Plasma Concentrations ◽  
Gel Filtration ◽  
Plasma Kallikrein ◽  
Peptide Substrate ◽  
Total Inhibition ◽  
Α2 Macroglobulin ◽  
Dependent Inhibition ◽  
Plus Fraction ◽  
Time Dependent Inhibition ◽  
Esterase Inhibitor

Plasma inhibitors of plasma kallikrein(KK) were studied using chromogenic peptide substrate assays. Both “immediate” and “time-dependent” inhibition was detected. Sephadex G-150 gel filtration revealed that fractions containing α2-macroglobulin (α2 M), C1 - esterase inhibitor (CIINH) and a low molecular weight component(KKI3) gave “immediate” inhibition. When fractions were tested for “total” inhibition (incubation of enzyme plus fraction for 300 seconds at 37°C) CIINH was found to be the major inhibitor. Both the α2M and KKI3-containing fractions exhibited more inhibition than in the “immediate” inhibition assay. Studies with purified preparations of CIINH and α2 M indicated that these are the two most important plasma inhibitors of KK. Preparations of α1-antitrypsin (α1AT), antithrombin III (ATIII) and α2-antiplasmin (α2AP) produced insignificant inhibition. When “total” KK inhibition in plasma samples from 20 healthy subjects was compared with plasma concentrations of CIINH, α2M and α1AT (immunochemical assays) a very good correlation (r=0.81) was found between percentage inhibition and CIINH concentration. Correlation values for the other antiproteases were α2M r=0.36 and α1AT r=0.19.

scholarly journals Reconstruction of input functions from a dynamic PET image with sequential administration of 15O2 and H215O for noninvasive and ultra-rapid measurement of CBF, OEF, and CMRO2

2017 ◽  
Vol 38 (5) ◽  
pp. 780-792 ◽  
Author(s):  
Nobuyuki Kudomi ◽  
Yukito Maeda ◽  
Hiroyuki Yamamoto ◽  
Yuka Yamamoto ◽  
Tetsuhiro Hatakeyama ◽  
...  
Keyword(s):  
Rate Constants ◽  
Human Subjects ◽  
Invasive Procedure ◽  
Invasive Technique ◽  
Invasive Approach ◽  
Non Invasive ◽  
Sequential Administration ◽  
Invasive Method ◽  
The Difference ◽  
Arterial Input Functions

CBF, OEF, and CMRO2 images can be quantitatively assessed using PET. Their image calculation requires arterial input functions, which require invasive procedure. The aim of the present study was to develop a non-invasive approach with image-derived input functions (IDIFs) using an image from an ultra-rapid O2 and C15O2 protocol. Our technique consists of using a formula to express the input using tissue curve with rate constants. For multiple tissue curves, the rate constants were estimated so as to minimize the differences of the inputs using the multiple tissue curves. The estimated rates were used to express the inputs and the mean of the estimated inputs was used as an IDIF. The method was tested in human subjects ( n = 24). The estimated IDIFs were well-reproduced against the measured ones. The difference in the calculated CBF, OEF, and CMRO2 values by the two methods was small (<10%) against the invasive method, and the values showed tight correlations ( r = 0.97). The simulation showed errors associated with the assumed parameters were less than ∼10%. Our results demonstrate that IDIFs can be reconstructed from tissue curves, suggesting the possibility of using a non-invasive technique to assess CBF, OEF, and CMRO2.

Combination of GSH Trapping and Time-Dependent Inhibition Assays as a Predictive Method of Drugs Generating Highly Reactive Metabolites

2011 ◽  
Vol 39 (7) ◽  
pp. 1247-1254 ◽  
Author(s):  
Shintaro Nakayama ◽  
Hideo Takakusa ◽  
Akiko Watanabe ◽  
Yoshihiro Miyaji ◽  
Wataru Suzuki ◽  
...  
Keyword(s):  
Time Dependent ◽  
Reactive Metabolites ◽  
Predictive Method ◽  
Dependent Inhibition ◽  
Time Dependent Inhibition
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