Discovery of a potent cyclooxygenase-2 inhibitor, S4, through docking-based pharmacophore screening, in vivo and in vitro estimations

Cyclooxygenase (COX; EC: 1.14.99.1), the key enzyme in prostaglandin production in the human body, is a major pharmacological target for developing anti-inflammatory agents.

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Heme Oxygenase-1, a Key Enzyme for the Cytoprotective Actions of Halophenols by Upregulating Nrf2 Expression via Activating Erk1/2 and PI3K/Akt in EA.hy926 Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/7028478 ◽

2017 ◽

Vol 2017 ◽

pp. 1-13 ◽

Cited By ~ 6

Author(s):

Xiu E. Feng ◽

Tai Gang Liang ◽

Jie Gao ◽

De Peng Kong ◽

Rui Ge ◽

...

Keyword(s):

Heme Oxygenase ◽

Antioxidant Activities ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Key Enzyme ◽

Ea.Hy926 Cells ◽

Anti Inflammatory ◽

Mechanistic Basis

Increasing evidence has demonstrated that heme oxygenase-1 (HO-1) is a key enzyme triggered by cellular stress, exhibiting cytoprotective, antioxidant, and anti-inflammatory abilities. Previously, we prepared a series of novel active halophenols possessing strong antioxidant activities in vitro and in vivo. In the present study, we demonstrated that these halophenols exhibited significant protective effects against H2O2-induced injury in EA.hy926 cells by inhibition of apoptosis and ROS and TNF-αproduction, as well as induction of the upregulation of HO-1, the magnitude of which correlated with their cytoprotective actions. Further experiments which aimed to determine the mechanistic basis of these actions indicated that the halophenols induced the activation of Nrf2, Erk1/2, and PI3K/Akt without obvious effects on the phosphorylation of p38, JNK, or the expression of PKC-δ. This was validated with the use of PD98059 and Wortmannin, specific inhibitors of Erk1/2 and PI3K, respectively. Overall, our study is the first to demonstrate that the cytoprotective actions of halophenols involve their antiapoptotic, antioxidant, and anti-inflammatory abilities, which are mediated by the upregulation of Nrf2-dependent HO-1 expression and reductions in ROS and TNF-αgeneration via the activation of Erk1/2 and PI3K/Akt in EA.hy926 cells. HO-1 may thus be an important potential target for further research into the cytoprotective actions of halophenols.

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Anti-nociceptive and Anti-inflammatory Activities of Asparacosin A Involve Selective Cyclooxygenase 2 and Inflammatory Cytokines Inhibition: An in-vitro, in-vivo, and in-silico Approach

Frontiers in Immunology ◽

10.3389/fimmu.2019.00581 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 3

Author(s):

Nasiara Karim ◽

Inamullah Khan ◽

Waheed Khan ◽

Imran Khan ◽

Ajmal Khan ◽

...

Keyword(s):

Inflammatory Cytokines ◽

In Silico ◽

Cyclooxygenase 2 ◽

Anti Inflammatory

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Study of Osteoarthritis Treatment with Anti-Inflammatory Drugs: Cyclooxygenase-2 Inhibitor and Steroids

BioMed Research International ◽

10.1155/2015/595273 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 25

Author(s):

Hongsik Cho ◽

Andrew Walker ◽

Jeb Williams ◽

Karen A. Hasty

Keyword(s):

Gene Expression ◽

Type Ii Collagen ◽

Cartilage Degradation ◽

Cyclooxygenase 2 ◽

Cox Inhibitor ◽

Inflammatory Drugs ◽

Cox 2 ◽

Anti Inflammatory

Patients with osteoarthritis (OA), a condition characterized by cartilage degradation, are often treated with steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) selective NSAIDs. Due to their inhibition of the inflammatory cascade, the drugs affect the balance of matrix metalloproteinases (MMPs) and inflammatory cytokines, resulting in preservation of extracellular matrix (ECM). To compare the effects of these treatments on chondrocyte metabolism, TNF-αwas incubated with cultured chondrocytes to mimic a proinflammatory environment with increasing production of MMP-1 and prostaglandin E2 (PGE2). The chondrocytes were then treated with either a steroid (prednisone), a nonspecific COX inhibitor NSAID (piroxicam), or a COX-2 selective NSAID (celecoxib). Both prednisone and celecoxib decreased MMP-1 and PGE-2 production while the nonspecific piroxicam decreased only the latter. Both prednisone and celecoxib decreased gene expression of MMP-1 and increased expression of aggrecan. Increased gene expression of type II collagen was also noted with celecoxib. The nonspecific piroxicam did not show these effects. The efficacy of celecoxibin vivowas investigated using a posttraumatic OA (PTOA) mouse model.In vivo, celecoxib increases aggrecan synthesis and suppresses MMP-1. In conclusion, this study demonstrates that celecoxib and steroids exert similar effects on MMP-1 and PGE2 productionin vitroand that celecoxib may demonstrate beneficial effects on anabolic metabolismin vivo.

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δ-Amyrone, a specific inhibitor of cyclooxygenase-2, exhibits anti-inflammatory effects in vitro and in vivo of mice

International Immunopharmacology ◽

10.1016/j.intimp.2014.04.019 ◽

2014 ◽

Vol 21 (1) ◽

pp. 112-118 ◽

Cited By ~ 10

Author(s):

Xiaofeng Niu ◽

Huan Yao ◽

Weifeng Li ◽

Qingli Mu ◽

Huani Li ◽

...

Keyword(s):

Specific Inhibitor ◽

Cyclooxygenase 2 ◽

Anti Inflammatory

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Computer simulation of the in vitro and in vivo anti-inflammatory activities of dihydropyrimidines acid derivatives through the inhibition of cyclooxygenase-2

Medicinal Chemistry Research ◽

10.1007/s00044-012-0244-2 ◽

2012 ◽

Vol 22 (5) ◽

pp. 2493-2504 ◽

Cited By ~ 1

Author(s):

Raksha Dhankar ◽

Anjali M. Rahatgaonkar ◽

Rakesh Shukla ◽

Mukund Chorghade ◽

Ashutosh Tiwari

Keyword(s):

Computer Simulation ◽

Cyclooxygenase 2 ◽

Anti Inflammatory

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Vitex agnus-castus L. (Chasteberry) extracts shows in vitro and in vivo anti-inflammatory and anti-tumor propensities via reduction of cyclooxygenase-2 activity and oxidative stress complications

South African Journal of Botany ◽

10.1016/j.sajb.2021.02.001 ◽

2021 ◽

Author(s):

Faten M. Ibrahim ◽

Abeer Y. Ibrahim ◽

Samah A. El-Newary ◽

Saber F. Hendawy ◽

Mohamad F. Mahomoodally

Keyword(s):

Oxidative Stress ◽

Cyclooxygenase 2 ◽

Agnus Castus ◽

Anti Inflammatory ◽

And Oxidative Stress

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Synthesis of 1,3-benzoxazines Based on 2,4,4-trimethyl-7,2’,4’-trihydroxy Flavan: Antibacterial, Anti-inflammatory, Cyclooxygenase-2 Inhibition and Molecular Modelling Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180420100922 ◽

2018 ◽

Vol 16 (1) ◽

pp. 58-65

Author(s):

Issam A. Mohammed ◽

Mahmood Ahmed ◽

Rabia Ikram ◽

Muhammad Muddassar ◽

Muhammad Abdul Qadir ◽

...

Keyword(s):

Condensation Reaction ◽

Binding Mode ◽

Antibacterial Activities ◽

Cyclooxygenase 2 ◽

Primary Amines ◽

Docking Simulations ◽

Cox 2 ◽

Anti Inflammatory

Background: In the present study, the formation of 2, 4, 4-trimethyl-7,2’4’-trihydroxy flavan has been used as the key feature for the formation of new 1,3-benzoxazines. This reaction was carried out via Mannich-condensation reaction, the 7-hydroxy group of flavan was reacted with different primary amines in the presence of formaldehyde. Methods: All the synthesized compounds were characterized on the basis of FT-IR, NMR, MS and elemental analysis (CHN). Disk diffusion and 96-well plate assay methods were employed for the zone of inhibition and minimum inhibitory concentration determination, respectively to investigate the antibacterial activities. Results and Conclusion: Our studies showed that compound with electron withdrawing group on the benzene ring of 1,3-benzoxazines has promising antibacterial activities. An oral dose of 10 mg/kg body weight was administered to albino mice for acute toxicity of synthesized compounds. In vivo anti-inflammatory and in-vitro cyclooxygenase-2 (COX-2) studies showed that compound 11 was the most potent anti-inflammatory agent which inhibited induced edema by 62.7% while 68.7% inhibition of COX-2 was observed. The plausible binding mode of this compound in COX-2 enzyme was also determined using molecular docking simulations.

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Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach

Pharmaceuticals ◽

10.3390/ph13090209 ◽

2020 ◽

Vol 13 (9) ◽

pp. 209 ◽

Cited By ~ 2

Author(s):

Rozires P. Leão ◽

Josiane V. Cruz ◽

Glauber V. da Costa ◽

Jorddy N. Cruz ◽

Elenilze F. B. Ferreira ◽

...

Keyword(s):

Binding Affinity ◽

Md Simulation ◽

Md Simulations ◽

Cyclooxygenase 2 ◽

In Vivo Studies ◽

Chemical Structures ◽

Anti Inflammatory ◽

Cyclooxygenase 2 Inhibitors

The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = −11.0 kcal/mol), LMQC36 (∆G = −10.6 kcal/mol), and LMQC50 (∆G = −10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = −10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = −45.31 kcal/mol; LMQC72: ΔGbind = −38.58 kcal/mol; LMQC36: ΔGbind = −36.10 kcal/mol; and LMQC50: ΔGbind = −39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand.

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