Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cingolani, Gino; Panella, Antonio; Perrone, Maria Grazia; Vitale, Paola; Mauro, Giuseppe Di; Fortuna, Cosimo G.; Armen, Roger S.; Ferorelli, Savina; Smith, William L.; Scilimati, Antonio

doi:10.1016/j.ejmech.2017.06.045

Cited by 67 publications

(61 citation statements)

References 42 publications

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“…This constriction opens up paving the way for substrates and inhibitors entry to the channel. The catalytic activity of COX-1 is mainly mediated by trapping arachidonic acid (AA) between residues Arg120, Tyr355 and the catalytic Tyr385 [33].…”

Section: Cycloxygenase-1mentioning

confidence: 99%

“…Furthermore, mofezolac is found to participate in hydrogen bonding to Tyr355. It is also surrounded by a rich set of hydrophobic residues in COX1 binding site, which explain its numerous van der Waal interactions [33]. Table 4.…”

Section: Cycloxygenase-1mentioning

confidence: 99%

“…Other inhibitors such as diclofenac and lumiracoxib, have been reported to bind in the same inverted conformation to Ser530 and Tyr385, highlighting the importance of those 2 residues in ligand association [32]. Contrary to COX-1, Arg120 mutation to an uncharged residue doesn't lead to detrimental loss of complex stability of COX-2 inhibitors, suggesting that interaction of arachidonic acid with Arg120 does not play a great role in COX-2 as it does in the case of COX-1 [33].…”

Section: Cycloxygenase-2 Proteinmentioning

confidence: 99%

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Thymus algeriensis and Thymus fontanesii: Chemical Composition, In Vivo Antiinflammatory, Pain Killing and Antipyretic Activities: A Comprehensive Comparison

et al. 2020

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This study aimed to investigate the chemical composition, and evaluate the antioxidant, anti-inflammatory, anti-pyretic, and the analgesic properties of methanol extracts from the leaves of Thymus algeriensis and Thymus fontanesii (Lamiaceae). Thirty-five secondary metabolites were characterized in both extracts using HPLC-PDA-ESI-MS/MS. Phenolic acids, mainly rosmarinic acid and its derivatives, dominated the T. algeriensis extract, while the phenolic diterpene carnosol and the methylated flavonoid salvigenin, prevailed in T. fontanesii extract. Molecular docking study was carried out to estimate the anti-inflammatory potential and the binding affinities of some individual secondary metabolites from both extracts to the main enzymes involved in the inflammation pathway. In vitro enzyme inhibitory assays and in vivo assays were used to investigate the antioxidant and anti-inflammatory activities of the extracts. Results revealed that both studied Thymus species exhibited antioxidant, anti-inflammatory, analgesic, and antipyretic effects. They showed to be a more potent antioxidant than ascorbic acid and more selective against cyclooxygenase (COX-2) than diclofenac and indomethacin. Relatively, the T. fontanesii extract was more potent as COX-2 inhibitor than T. algeriensis. In conclusion, Thymus algeriensis and Thymus fontanesii may be interesting candidates for the treatment of inflammation and oxidative stress-related disorders.

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Section: Cycloxygenase-1mentioning

confidence: 99%

Section: Cycloxygenase-1mentioning

confidence: 99%

Section: Cycloxygenase-2 Proteinmentioning

confidence: 99%

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Thymus algeriensis and Thymus fontanesii: Chemical Composition, In Vivo Antiinflammatory, Pain Killing and Antipyretic Activities: A Comprehensive Comparison

et al. 2020

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“…On the other hand, mofezolac 2 ( Fig. 1) was recently developed as selective COX-1 inhibitor with analgesic antiinflammatory potential and low ulcerogenic liability [13]. Mofezolac has also displayed promising anticancer activity in intestinal cancer [14,15].…”

Section: Introductionmentioning

confidence: 99%

Carprofen: a theoretical mechanistic study to investigate the impact of hydrophobic interactions of alkyl groups on modulation of COX-1/2 binding selectivity

Gouda

Almalki

2019

SN Appl. Sci.

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Development of selective COX-1 and COX-2 was successfully used to overcome GIT side effects of the classical NSAIDs. Currently, virtual screening and docking study were extensively used to design of new potent and safe drug candidates. In this study, four series of carprofen derivatives were designed by isosteric replacement of the-NH-with-O- ,-Sand-CH 2-groups. More than 90 derivatives bearing different alkyl substituents were designed in this study. AutoDock software was used to explore the binding mode, affinity and selectivity of the designed analogs to COX1/2. The results revealed that position and length of alkyl substituents have remarkable effect on the binding mode. Substitution with alkyl groups at C1 and C6 of the four scaffolds improved binding to COX-1, while at C4 enhanced COX-2 binding affinity. Compound 66 displayed the highest binding affinity for COX-1 and COX-2 with ΔG b of 11.2 and 10.15 kcal/mol, respectively. Compound 56 and 99 displayed the highest potential selectivity to COX-1 and COX-2, respectively. Drug-likeness study and synthetic accessibility were evaluated for the most promising analogs. Compound 29 displayed drug-likeness score (DLS) of 0.96 compared to 0.3 for carprofen. Taken together, these results highlighted the importance of hydrophobic interactions in modulation of COX-1/2 binding selectivity of new potential NSAIDs.

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“…To further investigate the mechanism of CoxFluor activation by COX‐2, we employed molecular dynamics (MD) and ensemble docking. Previous structures of COX‐1 (PDB 5U6X) and COX‐2 (PDB 5KIR) were selected, ligands were removed and the holoenzyme was simulated in explicit water over a period of 200 ns. Importantly, no global differences were observed for the peptide backbone across a panel of COX‐1 and COX‐2 structures, even in the presence of ligands and substrate (www.rcsb.org, all root‐mean‐standard‐deviation <2.5 Å, Tables S1–2 and Figure S5) .…”

Section: Resultsmentioning

confidence: 99%

An Activity‐Based Sensing Approach for the Detection of Cyclooxygenase‐2 in Live Cells

et al. 2020

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Cyclooxygenase‐2 (COX‐2) overexpression is prominent in inflammatory diseases, neurodegenerative disorders, and cancer. Directly monitoring COX‐2 activity within its native environment poses an exciting approach to account for and illuminate the effect of the local environments on protein activity. Herein, we report the development of CoxFluor, the first activity‐based sensing approach for monitoring COX‐2 within live cells with confocal microscopy and flow cytometry. CoxFluor strategically links a natural substrate with a dye precursor to engage both the cyclooxygenase and peroxidase activities of COX‐2. This catalyzes the release of resorufin and the natural product, as supported by molecular dynamics and ensemble docking. CoxFluor enabled the detection of oxygen‐dependent changes in COX‐2 activity that are independent of protein expression within live macrophage cells.

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Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cited by 67 publications

References 42 publications

Thymus algeriensis and Thymus fontanesii: Chemical Composition, In Vivo Antiinflammatory, Pain Killing and Antipyretic Activities: A Comprehensive Comparison

Thymus algeriensis and Thymus fontanesii: Chemical Composition, In Vivo Antiinflammatory, Pain Killing and Antipyretic Activities: A Comprehensive Comparison

Carprofen: a theoretical mechanistic study to investigate the impact of hydrophobic interactions of alkyl groups on modulation of COX-1/2 binding selectivity

An Activity‐Based Sensing Approach for the Detection of Cyclooxygenase‐2 in Live Cells

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