Goltsov Alexey, Lebedeva Galina, Humphery-Smith Ian, Goltsov Gregory, Demin Oleg, Goryanin Igor
Centre for Research in Informatics and Systems Pathology, School of Contemporary Sciences, University of Abertay Dundee, Dundee, DD1 1HG, UK.
Centre for Systems Biology at Edinburgh, University of Edinburgh, The King's Buildings, Edinburgh, EH9 3JZ, UK.
Pharmaceuticals (Basel). 2010 Jul 2;3(7):2059-2081. doi: 10.3390/ph3072059.
The detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy.
前列腺素H合酶-1（PGHS-1）的详细动力学模型被应用于对不同类型非甾体抗炎药（NSAIDs）剂量依赖性的计算机模拟筛选，这些药物包括：可逆/不可逆、对PGHS-1/PGHS-2非选择性/选择性以及时间依赖性/非依赖性抑制剂（阿司匹林、布洛芬、塞来昔布等）。计算机模拟筛选显示，同一药物的半数抑制浓度（IC50）存在显著差异，这取决于不同的体外和体内实验条件。为了研究NSAIDs抑制作用的这种高度异质性，我们开发了一种计算机模拟方法，以评估在不同PGHS-1微环境条件下（如花生四烯酸、还原辅因子和过氧化物浓度）NSAIDs对靶点的作用。所设计的技术能够将在一种实验设置中获得的药物IC值转换到另一种设置中，并根据相关的体外数据预测体内抑制作用。对于阿司匹林的情况，我们阐明了其疗效增强和降低（阿司匹林抵抗）的潜在机制，这取决于体外/体内实验设置中的PGHS-1微环境。我们还展示了两种NSAIDs组合作用（阿司匹林与布洛芬、阿司匹林与塞来昔布）的计算机模拟筛选结果，并研究了选择性和非选择性NSAIDs抑制阿司匹林介导的PGHS-1抑制作用的实验观察效应的机制。此外，我们讨论了所得结果在NSAIDs检测标准化问题、NSAIDs疗效对PGHS-1细胞环境的依赖性、耐药性以及NSAIDs联合治疗中的应用。
