In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1

Alexey Goltsov, Galina Lebedeva, Ian Humphery-Smith, Gregory Goltsov, Oleg Demin, Igor Goryanin

Research output: Contribution to journalSpecial issue

  • 5 Citations

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.
Original languageEnglish
Pages (from-to)2059-2081
Number of pages23
JournalPharmaceuticals
Volume3
Issue number7
DOIs
StatePublished - 2010

Fingerprint

Cyclooxygenase 1
Computer Simulation
Anti-Inflammatory Agents
Aspirin
In Vitro Techniques
Ibuprofen
Peroxides
Cyclooxygenase 2
Combination Drug Therapy
Drug Resistance
Arachidonic Acid
Inhibitory Concentration 50

Cite this

Goltsov, A., Lebedeva, G., Humphery-Smith, I., Goltsov, G., Demin, O., & Goryanin, I. (2010). In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1. Pharmaceuticals, 3(7), 2059-2081. DOI: 10.3390/ph3072059

Goltsov, Alexey; Lebedeva, Galina; Humphery-Smith, Ian; Goltsov, Gregory; Demin, Oleg; Goryanin, Igor / In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1.

In: Pharmaceuticals, Vol. 3, No. 7, 2010, p. 2059-2081.

Research output: Contribution to journalSpecial issue

@article{81897d9b5a3149478a5224baa1e660f9,
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.",
author = "Alexey Goltsov and Galina Lebedeva and Ian Humphery-Smith and Gregory Goltsov and Oleg Demin and Igor Goryanin",
year = "2010",
doi = "10.3390/ph3072059",
volume = "3",
pages = "2059--2081",
journal = "Pharmaceuticals",
issn = "1424-8247",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "7",

}

Goltsov, A, Lebedeva, G, Humphery-Smith, I, Goltsov, G, Demin, O & Goryanin, I 2010, 'In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1' Pharmaceuticals, vol 3, no. 7, pp. 2059-2081. DOI: 10.3390/ph3072059

In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1. / Goltsov, Alexey; Lebedeva, Galina; Humphery-Smith, Ian; Goltsov, Gregory; Demin, Oleg; Goryanin, Igor.

In: Pharmaceuticals, Vol. 3, No. 7, 2010, p. 2059-2081.

Research output: Contribution to journalSpecial issue

TY - JOUR

T1 - In Silico screening of nonsteroidal anti-inflammatory drugs and their combined action on Prostaglandin H Synthase-1

AU - Goltsov,Alexey

AU - Lebedeva,Galina

AU - Humphery-Smith,Ian

AU - Goltsov,Gregory

AU - Demin,Oleg

AU - Goryanin,Igor

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.3390/ph3072059

DO - 10.3390/ph3072059

M3 - Special issue

VL - 3

SP - 2059

EP - 2081

JO - Pharmaceuticals

T2 - Pharmaceuticals

JF - Pharmaceuticals

SN - 1424-8247

IS - 7

ER -

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. Available from, DOI: 10.3390/ph3072059