5-Heteroatom substituted pyrazoles as canine COX-2 inhibitors. Part III: Molecular modeling studies on binding contribution of 1-(5-methylsulfonyl)pyrid-2-yl and 4-nitrile

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 M, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents.

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DESIGN OF POTENTIAL CYCLOOXYGENASE INHIBITORS USING PHARMACOPHORE OPTIMIZATION BY MOLECULAR MODELING STUDIES

INDIAN DRUGS ◽

10.53879/id.52.12.10154 ◽

2015 ◽

Vol 52 (12) ◽

pp. 16-22

Author(s):

S. S Todkar ◽

◽

A. H. Hoshmani

Keyword(s):

Molecular Modeling ◽

Nearest Neighbor ◽

3D Qsar ◽

Field Analysis ◽

K Nearest Neighbor ◽

Qsar Studies ◽

2D Qsar ◽

Molecular Modeling Studies ◽

Cox 2 ◽

Cox 2 Inhibitors

Recently discovery of relation between cyclooxygenase–2 (COX–2) inhibition and prevention of growth of cansar cells is a major area for research in medicinal chemistry, as it is free from side effects which are genetically shown by developed anticancer agents. In an attempt to develop potent and nontoxic COX–2 inhibitors, we have optimized the 1,5- diaryl pyrazole pharmacophore by using molecular modeling studies. In this paper we present results of 2D and 3D QSAR studies of a series of 22 molecules containing 1,5- diaryl pyrazole pharmacophore as selective COX–2 inhibitors. The 3D QSAR studies were performed using two different methods, stepwise variable selection k–nearest neighbor molecular field analysis (SW kNN–MFA) and simulated annealing k–nearest neighbor molecular field analysis (SA kNN–MFA) methods. The 2D QSAR studies were performed using multiple regressions. 3D QSAR studies produced reasonably good predictive models with high cross–validated r2cv value of 0.732 and 0.783 and predicted r2 value of 0.882 and 0.794 values using the models SW kNN–MFA and SA kNN–MFA method, respectively, whereas the r2 & predicted r2 value in 2D QSAR studies was found to be 0.84914 & 0.9157, respectively. the 2D QSAR studies indicated contribution of different physicochemical descriptors and the result of 3D QSAR studies indicated the exact steric and electronic requirement in the ranges at various positions in the 1,5- diaryl pyrazole pharmacophore. The pharmacophore requirement for selective COX–2 inhibition was optimized and requirement at various positions around 1, 5- diaryl pyrazole pharmacophore were defined.

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Supramolecular Structure of Self-assembled Synthetic Zinc-131-oxo-chlorins Possessing a Primary, Secondary or Tertiary Alcoholic 31-Hydroxyl Group: Visible Spectroscopic and Molecular Modeling Studies¶

Photochemistry and Photobiology ◽

10.1562/0031-8655(2001)073<0153:ssosas>2.0.co;2 ◽

2001 ◽

Vol 73 (2) ◽

pp. 153 ◽

Cited By ~ 36

Author(s):

Shiki Yagai ◽

Tomohiro Miyatake ◽

Yoshiyuki Shimono ◽

Hitoshi Tamiaki

Keyword(s):

Molecular Modeling ◽

Supramolecular Structure ◽

Hydroxyl Group ◽

Modeling Studies ◽

Molecular Modeling Studies ◽

Self Assembled

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p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180816666181128112249 ◽

2020 ◽

Vol 17 (2) ◽

pp. 169-183 ◽

Cited By ~ 1

Author(s):

İrem Bozbey ◽

Suat Sari ◽

Emine Şalva ◽

Didem Kart ◽

Arzu Karakurt

Keyword(s):

Molecular Modeling ◽

Neuroblastoma Cell ◽

Neuroblastoma Cells ◽

Cytotoxic Agents ◽

Human Neuroblastoma Cell ◽

Human Neuroblastoma ◽

Modeling Studies ◽

Broth Microdilution Method ◽

Molecular Modeling Studies

Background: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immunecompromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells. Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions. Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling. Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 µM. In this line, 3 was the most potent with an IC50 value of 82.18 μM followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH. Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.

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Berberine, A Phytoalkaloid, Inhibits Inflammatory Response Induced by LPS through NF-Kappaβ Pathway: Possible Involvement of the IKKα

Molecules ◽

10.3390/molecules26164733 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4733

Author(s):

Kiran Reddi ◽

Hanxuan Li ◽

Wei Li ◽

Sarada Tetali

Keyword(s):

Arachidonic Acid ◽

Molecular Modeling ◽

Direct Interaction ◽

Ligand Binding Site ◽

Quantitative Real Time Pcr ◽

Tnf Α ◽

Molecular Modeling Studies ◽

Therapeutic Properties ◽

Cox 2 ◽

Activated Monocytes

Berberine (BBR), a plant alkaloid, is known for its therapeutic properties of anticancer, cardioprotective, antidiabetic, hypolipidemic, neuroprotective, and hepatoprotective activities. The present study was to determine the molecular mechanism of BBR’s pharmacological activity in human monocytic (THP-1) cells induced by arachidonic acid (AA) or lipopolysaccharide (LPS). The effect of BBR on AA/LPS activated proinflammatory markers including TNF-α, MCP-1, IL-8 and COX-2 was measured by ELISA or quantitative real-time PCR. Furthermore, the effect of BBR on LPS-induced NF-κB translocation was determined by immunoblotting and confocal microscopy. AA/ LPS-induced TNF-α, MCP-1, IL-6, IL-8, and COX-2 markers were markedly attenuated by BBR treatment in THP-1 cells by inhibiting NF-κB translocation into the nucleus. Molecular modeling studies suggested the direct interaction of BBR to IKKα at its ligand binding site, which led to the inhibition of the LPS-induced NF-κB translocation to the nucleus. Thus, the present study demonstrated the anti-inflammatory potential of BBR via NF-κB in activated monocytes, whose interplay is key in health and in the pathophysiology of atherosclerotic development in blood vessel walls. The present study findings suggest that BBR has the potential for treating various chronic inflammatory disorders.

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Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives

Molecules ◽

10.3390/molecules26123550 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3550

Author(s):

Katharigatta N. Venugopala ◽

Sandeep Chandrashekharappa ◽

Christophe Tratrat ◽

Pran Kishore Deb ◽

Rahul D. Nagdeve ◽

...

Keyword(s):

Molecular Modeling ◽

Graphical Representation ◽

Hydrophobic Interactions ◽

Basis Set ◽

Monoclinic Crystal ◽

X Ray ◽

Cox Inhibitors ◽

Design And Synthesis ◽

Cox 2 ◽

Cox 2 Inhibitors

The cyclooxygenase-2 (COX-2) enzyme is an important target for drug discovery and development of novel anti-inflammatory agents. Selective COX-2 inhibitors have the advantage of reduced side-effects, which result from COX-1 inhibition that is usually observed with nonselective COX inhibitors. In this study, the design and synthesis of a new series of 7-methoxy indolizines as bioisostere indomethacin analogues (5a–e) were carried out and evaluated for COX-2 enzyme inhibition. All the compounds showed activity in micromolar ranges, and the compound diethyl 3-(4-cyanobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5a) emerged as a promising COX-2 inhibitor with an IC50 of 5.84 µM, as compared to indomethacin (IC50 = 6.84 µM). The molecular modeling study of indolizines indicated that hydrophobic interactions were the major contribution to COX-2 inhibition. The title compound diethyl 3-(4-bromobenzoyl)-7-methoxyindolizine-1,2-dicarboxylate (5c) was subjected for single-crystal X-ray studies, Hirshfeld surface analysis, and energy framework calculations. The X-ray diffraction analysis showed that the molecule (5c) crystallizes in the monoclinic crystal system with space group P 21/n with a = 12.0497(6)Å, b = 17.8324(10)Å, c = 19.6052(11)Å, α = 90.000°, β = 100.372(1)°, γ = 90.000°, and V = 4143.8(4)Å3. In addition, with the help of Crystal Explorer software program using the B3LYP/6-31G(d, p) basis set, the theoretical calculation of the interaction and graphical representation of energy value was measured in the form of the energy framework in terms of coulombic, dispersion, and total energy.

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