Goltsov Alexey, Maryashkin Anton, Swat Maciej, Kosinsky Yuri, Humphery-Smith Ian, Demin Oleg, Goryanin Igor, Lebedeva Galina
Centre for Systems Biology at Edinburgh, University of Edinburgh, Scotland, United Kingdom.
Eur J Pharm Sci. 2009 Jan 31;36(1):122-36. doi: 10.1016/j.ejps.2008.10.015. Epub 2008 Nov 5.
The detailed kinetic model of Prostaglandin H Synthase-1 (COX-1) was developed to in silico test and predict inhibition effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on target. The model takes into account key features of the complex catalytic mechanism of cyclooxygenase-1, converting arachidonic acid to prostaglandin PGH(2), and includes the description of the enzyme interaction with various types of NSAIDs (reversible/irreversible, non-selective and selective to COX-1/COX-2). Two different versions of the model were designed to simulate the inhibition of COX-1 by NSAIDs in two most popular experimental settings - in vitro studies with purified enzyme, and the experiments with platelets. The developed models were applied to calculate the dose-dependence of aspirin and celecoxib action on COX- 1 in vitro and in vivo conditions. The mechanism of the enhancement of aspirin efficiency in platelet as compared to its action on purified COX-1 was elucidated. The dose-dependence of celecoxib simulated with the use of the "in vivo" version of the model predicted potentially strong inhibitory effect of celecoxib on thromboxan production in platelets. Simulation of the combined effect of two NSAIDs, aspirin and celecoxib, on COX-1 allowed us to reveal the mechanism underlying the suppression of aspirin-mediated COX-1 inhibition by celecoxib. We discuss our modelling results in the context of the on-going debates on the potential cardio-vascular risks associated with co-administration of various types of NSAIDs.
前列腺素H合成酶-1（COX-1）的详细动力学模型被开发出来，用于在计算机上测试和预测非甾体抗炎药（NSAIDs）对靶点的抑制作用。该模型考虑了环氧化酶-1将花生四烯酸转化为前列腺素PGH2的复杂催化机制的关键特征，并包括了该酶与各种类型NSAIDs（可逆/不可逆、非选择性以及对COX-1/COX-2选择性）相互作用的描述。设计了两个不同版本的模型来模拟在两种最常见实验环境中NSAIDs对COX-1的抑制作用——使用纯化酶的体外研究以及血小板实验。所开发的模型被用于计算阿司匹林和塞来昔布在体外和体内条件下对COX-1作用的剂量依赖性。阐明了阿司匹林在血小板中的效率与其对纯化COX-1的作用相比增强的机制。使用模型的“体内”版本模拟的塞来昔布剂量依赖性预测了塞来昔布对血小板中血栓素产生的潜在强烈抑制作用。模拟阿司匹林和塞来昔布这两种NSAIDs对COX-1的联合作用使我们能够揭示塞来昔布抑制阿司匹林介导的COX-1抑制作用的潜在机制。我们在关于各种类型NSAIDs联合使用潜在心血管风险的持续争论背景下讨论我们的建模结果。
