Fluorescent indomethacin-dansyl conjugates utilize the membrane-binding domain of cyclooxygenase-2 to block the opening to the active site

Xu, Shu; Uddin, Md. Jashim; Banerjee, Surajit; Duggan, Kelsey C.; Musee, Joel; Kiefer, James R.; Ghebreselasie, Kebreab; Rouzer, Carol A.; Marnett, Lawrence J.

doi:10.1074/jbc.ra119.007405

Cited by 24 publications

(31 citation statements)

References 38 publications

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“…This finding is consistent with the difference in solvent accessible surfaces harbored within each cyclooxygenase active site . CoxFluor also docks in a similar location to the reported indomethacin fluorescent inhibitors (Figure S7), further supporting the proposed cyclooxyenase‐dependent release of resorufin (Scheme b).…”

Section: Resultssupporting

confidence: 85%

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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Section: Resultssupporting

confidence: 85%

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

et al. 2020

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“…Crystal structures of both conjugate 1 (PDB 6BL4, Figure 17 A) and conjugate 2 (PDB 6BL3, Figure 17 B) complexed with COX-2 and Fe 3+ -protoporphyrin IX were obtained at 2.2 Å resolution. 113 In both cases, the indomethacin portion of the molecules adopts a binding pose similar to that of the parent compound in COX-2. A notable exception is the failure of the inhibitor to establish a contact with Arg-120 and displacement of that residue to provide room for the linker to pass through the constriction.…”

Section: Interactions Of Cox Proteins With Inhibitorsmentioning

confidence: 99%

“…The dansyl moieties of the two conjugates adopt very similar poses in the lobby region, establishing hydrophobic contacts with Val-89 and Leu-93, and a hydrogen bond links an oxygen atom of the dansyl sulfonyl group to the side chain of Ser-119. 113 …”

Section: Interactions Of Cox Proteins With Inhibitorsmentioning

confidence: 99%

Structural and Chemical Biology of the Interaction of Cyclooxygenase with Substrates and Non-Steroidal Anti-Inflammatory Drugs

Rouzer

Marnett

2020

Chem. Rev.

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Cyclooxgenases are key enzymes of lipid signaling. They carry out the first step in the production of prostaglandins, important mediators of inflammation, pain, cardiovascular disease, and cancer, and they are the molecular targets for nonsteroidal anti-inflammatory drugs, which are among the oldest and most chemically diverse set of drugs known. Homodimeric proteins that behave as allosterically modulated, functional heterodimers, the cyclooxygenases exhibit complex kinetic behavior, requiring peroxide-dependent activation and undergoing suicide inactivation. Due to their important physiological and pathophysiological roles and keen interest on the part of the pharmaceutical industry, the cyclooxygenases have been the focus of a vast array of structural studies, leading to the publication of over 80 crystal structures of the enzymes in complex with substrates or inhibitors supported by a wealth of functional data generated by site-directed mutation experiments. In this review, we explore the chemical biology of the cyclooxygenases through the lens of this wealth of structural and functional information. We identify key structural features of the cyclooxygenases, break down their active site into regional binding pockets to facilitate comparisons between structures, and explore similarities and differences in the binding modes of the wide variety of ligands (both substrates and inhibitors) that have been characterized in complex with the enzymes. Throughout, we correlate structure with function whenever possible. Finally, we summarize what can and cannot be learned from the currently available structural data and discuss the critical intriguing questions that remain despite the wealth of information that has been amassed in this field.

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“…For example, transformation of the acidic COOH group in indomethacin and formation of amide linkage resulted in producing compound II (Figure 1), which was 10 times more potent as a COX‐2 inhibitor than fluorocoxibs. [ 7 ] Also, naproxen derivatives ( III–VI ) (Figure 1) [ 8–10 ] were synthesized in which the ulcer effect was reduced as compared with the standard drug. Furthermore, selective COX‐2 inhibitors (coxibs) as celecoxib, rofecoxib, and valdecoxib were developed to overcome the nonselective drawbacks, but unfortunately, rofecoxib and valdecoxib were found to cause myocardial infarction and high blood pressure; therefore, their clinical use was terminated.…”

Section: Introductionmentioning

confidence: 99%

“…Chemical structures of traditional NSAIDs (indomethacin 1 and naproxen I ) and some reported modified indomethacin and naproxen amide derivatives ( II–VI ) [ 7–10 ] as selective COX‐2 inhibitors…”

Section: Introductionmentioning

confidence: 99%

New indomethacin analogs as selective COX‐2 inhibitors: Synthesis, COX‐1/2 inhibitory activity, anti‐inflammatory, ulcerogenicity, histopathological, and docking studies

Abdellatif

Abdelall

Elshemy

et al. 2020

Archiv der Pharmazie

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New indomethacin analogs 4a–g, 5, 6, 8a, and 8b were synthesized to overcome the nonselectivity and ulcer liability of indomethacin. All newly synthesized compounds were more potent against cyclooxygenase 2 (COX‐2; IC50 value range: 0.09–0.4 μМ) as compared with celecoxib (IC50 = 0.89 μМ). Compounds 4a, 4b, 4d, 5, and 6 showed the highest COX‐2 selectivity index (SI range = 4.07–6.33) as compared with indomethacin (SI = 1.14) and celecoxib (SI = 3.52). Additionally, 4a, 4b, 4d, 5, and 7 showed good anti‐inflammatory activity with edema inhibition (79.36–88.8%), relative to celecoxib (78.96%) and indomethacin (90.43%), after 5 h. Also, ulcerogenic effects and histopathological examination were assessed for the most potent analogs, 4b, 4d, 5, and 6, to determine their safety. The results can shed light on indomethacin analog 5 as a remarkable anti‐inflammatory lead compound with a good safety profile (ulcer index = 10.62) close to the nonulcerogenic drug celecoxib (ulcer index = 10.53) and better than indomethacin (ulcer index = 18.50). Docking studies were performed in the COX‐2 active site for the most active compounds, to test their selectivity and to confirm their mechanism of action.

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Fluorescent indomethacin-dansyl conjugates utilize the membrane-binding domain of cyclooxygenase-2 to block the opening to the active site

Cited by 24 publications

References 38 publications

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

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

Structural and Chemical Biology of the Interaction of Cyclooxygenase with Substrates and Non-Steroidal Anti-Inflammatory Drugs

New indomethacin analogs as selective COX‐2 inhibitors: Synthesis, COX‐1/2 inhibitory activity, anti‐inflammatory, ulcerogenicity, histopathological, and docking studies

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