Temperature Effects on Kinetics of hERG Drug Block: Implications for In Silico Proarrhythmic Risk Prediction

2017 ◽  
Vol 88 ◽  
pp. 203
Author(s):  
Monique Windley ◽  
Stefan Mann ◽  
Jamie Vandenberg ◽  
Adam Hill
Keyword(s):  
Risk Prediction ◽  
In Silico ◽  
Temperature Effects ◽  
Proarrhythmic Risk ◽  
Kinetics Of

scholarly journals Temperature Effects on Kinetics of KV11.1 Drug Block Have Important Consequences for In Silico Proarrhythmic Risk Prediction

2016 ◽  
Vol 90 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Monique J. Windley ◽  
Stefan A. Mann ◽  
Jamie I. Vandenberg ◽  
Adam P. Hill
Keyword(s):  
Risk Prediction ◽  
In Silico ◽  
Temperature Effects ◽  
Proarrhythmic Risk ◽  
Kinetics Of

F-to-O transition of cytochrome c oxidase: pH and temperature effects on the kinetics of charge translocation

2000 ◽  
Vol 28 (5) ◽  
pp. A469-A469 ◽  
Author(s):  
S. Siletsky ◽  
D. Zaslavsky ◽  
I. Smirnova ◽  
A. Kaulen ◽  
A. Konstantinov
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Temperature Effects ◽  
Charge Translocation ◽  
Kinetics Of

Estimation of uncertainty in multi-level in silico models predicting biomarkers of drug-induced proarrhythmic risk

2021 ◽  
Vol 350 ◽  
pp. S64-S65
Author(s):  
K. Kopanska ◽  
J.C. Gómez-Tamayo ◽  
J. Llopis-Lorente ◽  
B.A. Trenor-Gomis ◽  
J. Sáiz ◽  
...  
Keyword(s):  
In Silico ◽  
Drug Induced ◽  
Proarrhythmic Risk ◽  
Multi Level ◽  
In Silico Models ◽  
Estimation Of Uncertainty

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.

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