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 PGG2 and final PGH2 products under wide experimental conditions. In the paper we provided the 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.

中文翻译：

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前列腺素H合酶1的循环网络模型

开发了前列腺素H合酶-1（PGHS-1）的动力学模型，以研究其复杂的网络动力学和非甾体抗炎药（NSAID）在不同的体内和体外条件下的功效。为了正确描述PGHS-1催化的复杂机制，我们开发了一种微观方法来对酶的24种中间状态之间35个酶内部反应的复杂网络动力学进行建模。开发的模型定量描述了环氧合酶和过氧化物酶活性之间的相互关系。底物（花生四烯酸，AA）和减少共底物的竞争性消费；酶自灭活；AA的自催化作用；酶活化阈值，以及在广泛的实验条件下合成中间体PGG2和最终PGH2产物。在本文中，我们提供了酶催化循环的详细说明，基于一系列体外动力学数据的模型校准以及使用有关PGHS-1调控特性的实验数据进行的模型验证。经过验证的具有统一动力学参数集的PGHS-1模型可用于计算机筛选和预测NSAIDs及其组合对血栓形成前（血栓烷）和抗血栓形成（前列环素）前列腺素生物合成的平衡的抑制作用在表达PGHS-1的血小板和内皮细胞中的表达。