Pharmaceuticals 2010, 3(7), 2059-2081; doi:10.3390/ph3072059
Article

In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1

1,* email, 2email, 3email, 4email, 5,6email and 1,4email
Received: 4 May 2010; in revised form: 24 May 2010 / Accepted: 23 June 2010 / Published: 2 July 2010
(This article belongs to the collection Non-Steroidal Anti-Inflammatory Drugs)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: kinetic modeling; COX-1,2; NSAID; aspirin resistance; NSAID combination
PDF Full-text Download PDF Full-Text [783 KB, uploaded 2 July 2010 11:30 CEST]

Export to BibTeX |
EndNote


MDPI and ACS Style

Goltsov, A.; Lebedeva, G.; Humphery-Smith, I.; Goltsov, G.; Demin, O.; Goryanin, I. In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1. Pharmaceuticals 2010, 3, 2059-2081.

AMA Style

Goltsov A, Lebedeva G, Humphery-Smith I, Goltsov G, Demin O, Goryanin I. In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1. Pharmaceuticals. 2010; 3(7):2059-2081.

Chicago/Turabian Style

Goltsov, Alexey; Lebedeva, Galina; Humphery-Smith, Ian; Goltsov, Gregory; Demin, Oleg; Goryanin, Igor. 2010. "In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1." Pharmaceuticals 3, no. 7: 2059-2081.

Pharmaceuticals EISSN 1424-8247 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert