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Title: In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1
Authors: Goltsov, Alexey
Lebedeva, Galina
Humphery-Smith, Ian
Goltsov, Gregory
Demin, Oleg
Goryanin, Igor
Affiliation: University of Abertay Dundee. School of Contemporary Sciences
Keywords: Kinetic modeling
Aspirin resistance
NSAID combination
Issue Date: 2010
Publisher: MDPI Publishing
Type: Journal Article
Refereed: peer-reviewed
Rights: This is the publisher's version of this article, reproduced by permission of the publisher. Published version (c)MDPI Publishing, available from http://dx.doi.org/10.3390/ph3072059
Citation: Goltsov, A., et al. 2010. In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1. Pharmaceuticals. 3(7): pp.2059-2081. Available from: http://dx.doi.org/10.3390/ph3072059
Abstract: 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 IC50, 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.
URI: http://hdl.handle.net/10373/643
ISSN: 1424-8247
Appears in Collections:Science Engineering & Technology Collection

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