Binding kinetics of fluorescent bisphosphonates as a tool for monitoring bone dynamics in vivo

2013 ◽  
Author(s):  
Robert Tower ◽  
Graeme Campbell ◽  
Marc Muller ◽  
Olga Will ◽  
Frederieka Grundmann ◽  
...  
Keyword(s):  
Binding Kinetics ◽  
Kinetics Of ◽  
Bone Dynamics

scholarly journals Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

2021 ◽  
Author(s):  
Marco Niello ◽  
Spyridon Sideromenos ◽  
Ralph Gradisch ◽  
Ronan O'Shea ◽  
Jakob Schwazer ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
In Silico ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Irreversible Binding ◽  
Fast Kinetics ◽  
Slow Dissociation ◽  
Kinetics Of

Abstract α-Pyrrolidinovalerophenone (αPVP) is a psychostimulant and drug of abuse associated with severe intoxications in humans. αPVP exerts long-lasting psychostimulant effects, when compared to the classical dopamine transporter (DAT) inhibitor cocaine. Here, we compared the two enantiomeric forms of αPVP, the R- and the S-αPVP, with cocaine using a combination of in silico, in vitro and in vivo approaches. We found that αPVP enantiomers substantially differ from cocaine in their binding kinetics. The two enantiomers differ from each other in their association rates. However, they show similar slow dissociation rates leading to pseudo-irreversible binding kinetics at DAT. The pseudo-irreversible binding kinetics of αPVP is responsible for the observed non-competitive pharmacology and it correlates with persistent psychostimulant effects in mice. Thus, the slow binding kinetics of αPVP enantiomers profoundly differ from the fast kinetics of cocaine both in vitro and in vivo, suggesting drug-binding kinetics as a potential driver of psychostimulant effects in vivo.

Kinetics of Drug Binding and Residence Time

2019 ◽  
Vol 70 (1) ◽  
pp. 143-171 ◽  
Author(s):  
Mattia Bernetti ◽  
Matteo Masetti ◽  
Walter Rocchia ◽  
Andrea Cavalli
Keyword(s):  
Computational Methods ◽  
Residence Time ◽  
Drug Target ◽  
Early Stage ◽  
Kinetic Constant ◽  
Theoretical Background ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Kinetics Of

The kinetics of drug binding and unbinding is assuming an increasingly crucial role in the long, costly process of bringing a new medicine to patients. For example, the time a drug spends in contact with its biological target is known as residence time (the inverse of the kinetic constant of the drug-target unbinding, 1/ koff). Recent reports suggest that residence time could predict drug efficacy in vivo, perhaps even more effectively than conventional thermodynamic parameters (free energy, enthalpy, entropy). There are many experimental and computational methods for predicting drug-target residence time at an early stage of drug discovery programs. Here, we review and discuss the methodological approaches to estimating drug binding kinetics and residence time. We first introduce the theoretical background of drug binding kinetics from a physicochemical standpoint. We then analyze the recent literature in the field, starting from the experimental methodologies and applications thereof and moving to theoretical and computational approaches to the kinetics of drug binding and unbinding. We acknowledge the central role of molecular dynamics and related methods, which comprise a great number of the computational methods and applications reviewed here. However, we also consider kinetic Monte Carlo. We conclude with the outlook that drug (un)binding kinetics may soon become a go/no go step in the discovery and development of new medicines.

Binding Kinetics of a Fluorescently Labeled Bisphosphonate as a Tool for Dynamic Monitoring of Bone Mineral Deposition In Vivo

2014 ◽  
Vol 29 (9) ◽  
pp. 1993-2003 ◽  
Author(s):  
Robert J Tower ◽  
Graeme M Campbell ◽  
Marc Müller ◽  
Olga Will ◽  
Claus C Glüer ◽  
...  
Keyword(s):  
Bone Mineral ◽  
Binding Kinetics ◽  
Dynamic Monitoring ◽  
Mineral Deposition ◽  
Kinetics Of

Binding And Metabolisation Of PGI2 By Erythrocytes

1981 ◽  
Author(s):  
Ch Willems ◽  
J A van Mourik ◽  
H V Stel ◽  
W G van Aken
Keyword(s):  
Whole Blood ◽  
Blood Cells ◽  
Serotonin Release ◽  
Binding Kinetics ◽  
Plasma Binding ◽  
Autologous Plasma ◽  
Physiological Conditions ◽  
Platelet Inhibitor ◽  
Kinetics Of

Prostacyclin (PGI2) is rapidly hydrolysed in aqueous solution at neutral pH. Previously we have reported that PGI2 is stabilized by plasma components; yet PGI2 is rapidly metabolized in vivo. These findings prompted us to study the fate of PGI2 upon incubation in whole blood. The data on the distribution of PGI2 between blood cells and plasma indicate that PGI2 not only binds to platelets but also to erythrocytes. The Kinetics of binding were studied in more detail by incubating [3H] PGI2 at 37°C with washed erythrocytes resuspended in autologous plasma. Binding of [3H] PGI2 plateaued within 2 min. and was concentration dependant. The binding of [3H] PGI2 was not influenced by PGE1 or 6 keto PGF1α. [3H] 6 keto PGF1α showed no substantial binding to erythrocytes when compared with [3H] PGI2. Upon repeated incubation of [3H] PGI2 with erythrocytes less binding occured than would have Been expected from time and concentration dependancy. The latter finding is explained by the demonstration of breakdown of [3H] PGI2 - most likely into [3H] 6 keto-PGF1α - and by measurements of the biological activity of PGI2 Although metabol isation of PGI2 complicates the evaluation of binding kinetics it coufd be shown, by using inhibition of platelet serotonin release, that erythrocytes and platelets compete for PGI2. Binding of PGI2 to erythrocytes and subsequent metabolisation explains the apparent lability of PGI2 in whole blood. It is to expected that under physiological conditions erythrocytes suppress the effectiveness of PGI2 to act as a circulating platelet inhibitor.

scholarly journals Impact of real-time shedding on binding kinetics of membrane-remaining L-selectin to PSGL-1

2019 ◽  
Vol 316 (5) ◽  
pp. C678-C689 ◽  
Author(s):  
Shuang Peng ◽  
Shen-Bao Chen ◽  
Lin-Da Li ◽  
Chun-Fang Tong ◽  
Ning Li ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Real Time ◽  
Jurkat Cells ◽  
Binding Kinetics ◽  
Time Dependent ◽  
Intact Cells ◽  
The Impact ◽  
Kinetics Of

L-selectin shedding induced by various cytokines is crucial in activating neutrophils (PMNs) in inflammatory cascade. While the real-time shedding in vivo lasts ~10 min after PMN activation, the impact of time-dependent shedding on binding kinetics of membrane-remaining L-selectins to its ligands is poorly understood at transient or steady state. Here, we developed an in vitro L-selectin shedding dynamics approach, together with competitive assays of cell adhesion, and proposed a theoretical model for quantifying the impact of real-time shedding on the binding kinetics of membrane-remaining L-selectins to P-selectin glycoprotein ligand-1 (PSGL-1). Our data indicated that the extent of L-selectin shedding on PMA activation is higher, but the terminating time is longer for Jurkat cells than those for human PMNs. Meanwhile, fMLF or IL-8 stimulation yields the longer terminating time than that on PMA stimulation but results in a similar shedding extent for PMNs. L-selectin shedding reduces L-selectin-PSGL-1-mediated cell adhesion in three ways: decreasing membrane-anchored L-selectins, increasing soluble L-selectins competitively binding to ligands, and presenting conformational alteration of membrane-remaining L-selectins themselves. Compared with those on intact cells, the binding affinities of membrane-remaining L-selectin-PSGL-1 pairs were all enhanced at initial and lowered at the late shedding phase for both PMN and Jurkat cells even with varied transition time points. The rolling velocities of both PMNs and Jurkat cells were increased following mechanically or biochemically induced shedding of L-selectin under shear flow. These findings help to further our understanding of the function of time-dependent L-selectin shedding during the inflammation cascade.

Comparison of the binding kinetics of antibody-targeted N-(2-hydroxypropyl) methacrylamide (HPMA)-bound doxorubicin in vitro and in vivo

1996 ◽  
Vol 42 (3) ◽  
pp. 229-236 ◽  
Author(s):  
Marek Št'astný ◽  
Blanka Říhová ◽  
Jiří Strohalm ◽  
Karel Ulbrich
Keyword(s):  
Binding Kinetics ◽  
Hydroxypropyl Methacrylamide ◽  
Kinetics Of

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

Hepatobiliary Kinetics of 113mIn-Phenolphthalexon

1981 ◽  
Vol 20 (02) ◽  
pp. 90-93
Author(s):  
P.B. Parab ◽  
U.R. Raikar ◽  
R.D. Ganatra ◽  
M. C. Patel
Keyword(s):  
Biliary Excretion ◽  
Iminodiacetic Acid ◽  
Organ Distribution ◽  
Liver Uptake ◽  
On Line ◽  
Rapid Clearance ◽  
Chemical Purity ◽  
Kinetics Of ◽  
High Liver

Phenolphthalexon, a compound with iminodiacetic acid as a functional group, has been labelled with 113mIn to high chemical purity and its usefulness in studies of biliary excretion patency has been studied. Organ distribution of 113mIn-phenolphthalexon in mice was characterized by high liver uptake (50.8% of the administered dose after 5 min) and rapid clearance through the gall bladder. An animal model for studying obstruction of biliary excretion has been developed. Data on the kinetics of the radiopharmaceutical were obtained by collecting in-vivo data through an on-line computer.

Continuous Quantitative Monitoring of Mural, Platelet-Dependent, Thrombus Kinetics in the Crushed Rat Femoral Vein

1991 ◽  
Vol 65 (04) ◽  
pp. 425-431 ◽  
Author(s):  
F Stockmans ◽  
H Deckmyn ◽  
J Gruwez ◽  
J Vermylen ◽  
R Acland
Keyword(s):  
Thrombus Formation ◽  
Femoral Vein ◽  
Maximum Size ◽  
Digital Analysis ◽  
Video Recordings ◽  
Quantitative Monitoring ◽  
Set Up ◽  
Kinetics Of ◽  
Quantitative Nature

SummaryA new in vivo method to study the size and dynamics of a growing mural thrombus was set up in the rat femoral vein. The method uses a standardized crush injury to induce a thrombus, and a newly developed transilluminator combined with digital analysis of video recordings. Thrombi in this model formed rapidly, reaching a maximum size 391 ± 35 sec following injury, after which they degraded with a half-life of 197 ± 31 sec. Histological examination indicated that the thrombi consisted mainly of platelets. The quantitative nature of the transillumination technique was demonstrated by simultaneous measurement of the incorporation of 111In labeled platelets into the thrombus. Thrombus formation, studied at 30 min interval in both femoral veins, showed satisfactory reproducibility overall and within a given animalWith this method we were able to induce a thrombus using a clinically relevant injury and to monitor continuously and reproducibly the kinetics of thrombus formation in a vessel of clinically and surgically relevant size

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