title: In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1.
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.
authors.affiliation: Centre for Research in Informatics and Systems Pathology, School of Contemporary Sciences, University of Abertay Dundee, Dundee, DD1 1HG, UK. alexey.goltsov@gmail.com.
authors.forename: Alexey
authors.initials: A
authors.lastname: Goltsov
authors.affiliation: Centre for Systems Biology at Edinburgh, University of Edinburgh, The King's Buildings, Edinburgh, EH9 3JZ, UK. glebedev@staffmail.ed.ac.uk.
authors.forename: Galina
authors.initials: G
authors.lastname: Lebedeva
authors.affiliation: Deomed, 21 Emblehope Drive, Gosforth, Newcastle-upon-Tyne, NE3 4RW, UK. ianhs@hotmail.com.
authors.forename: Ian
authors.initials: I
authors.lastname: Humphery-Smith
authors.affiliation: School of Informatics, University of Edinburgh, Edinburgh, EH8 9AB, UK. g.goltsov@sms.ed.ac.uk.
authors.forename: Gregory
authors.initials: G
authors.lastname: Goltsov
authors.affiliation: Institute for Systems Biology SPb, Sankt-Peterburg, Toresa 80-48, Russia. demin@insysbio.ru.|A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119992, Russia. demin@insysbio.ru.
authors.forename: Oleg
authors.initials: O
authors.lastname: Demin
authors.affiliation: Centre for Research in Informatics and Systems Pathology, School of Contemporary Sciences, University of Abertay Dundee, Dundee, DD1 1HG, UK. goryanin@inf.ed.ac.uk.|School of Informatics, University of Edinburgh, Edinburgh, EH8 9AB, UK. goryanin@inf.ed.ac.uk.
authors.forename: Igor
authors.initials: I
authors.lastname: Goryanin
keywords: COX-1,2; NSAID; NSAID combination; aspirin resistance; kinetic modeling