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Open AccessArticle

Cycle Network Model of Prostaglandin H Synthase-1

1
Biocybernetics Systems and Technologies Division, Russian Technological University (MIREA), 119454 Moscow, Russia
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Simcyp PBPK Modeling and Simulation, Certara, Sheffield S1 2BJ, UK
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Modeling & Simulation Decisions LLD, 125167 Moscow, Russia
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Computational Oncology Group, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(10), 265; https://doi.org/10.3390/ph13100265
Received: 12 August 2020 / Revised: 16 September 2020 / Accepted: 17 September 2020 / Published: 23 September 2020
The kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in different in vitro and in vivo conditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold; and synthesis of intermediate prostaglandin G2 (PGG2) and final prostaglandin H2 (PGH2) products under wide experimental conditions. In the paper, we provide a detailed description of the enzyme catalytic cycle, model calibration based on a series of in vitro kinetic data, and model validation using experimental data on the regulatory properties of PGHS-1. The validated model of PGHS-1 with a unified set of kinetic parameters is applicable for in silico screening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1. View Full-Text
Keywords: PGHS-1; COX-1; NSAID; network model; enzyme regulation PGHS-1; COX-1; NSAID; network model; enzyme regulation
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Goltsov, A.; Swat, M.; Peskov, K.; Kosinsky, Y. Cycle Network Model of Prostaglandin H Synthase-1. Pharmaceuticals 2020, 13, 265.

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