14 results on '"Cyclooxygenase Inhibitors"'
Search Results
2. Anti-inflammatory drug approach: Synthesis and biological evaluation of novel pyrazolo[3,4-d]pyrimidine compounds.
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Atatreh, Noor, Youssef, Amal M., Ghattas, Mohammad A., Al Sorkhy, Mohammad, Alrawashdeh, Sara, Al-Harbi, Khaled B., El-Ashmawy, Ibrahim M., Almundarij, Tariq I., Abdelghani, Amani A., and Abd-El-Aziz, Alaa S.
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PYRIMIDINES , *DRUG synthesis , *BIOSYNTHESIS , *ANTI-inflammatory agents , *CYCLOOXYGENASE inhibitors , *ACYL chlorides - Abstract
The present work describes the design and synthesis of novel series of ten pyrazolo[3,4- d ]pyrazolo derivatives. Four compounds 3a , 3d , 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available cyclooxygenase-2 inhibitor celecoxib. They are even more potent than non-sterodial anti-inflammatory drug cyclooxygenase inhibitor diclofenac sodium. Our best hit 4d appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. The in silico findings come in line with the in vitro and in vivo assay results and also suggest that these compounds have the potetntial to be COX-2 selective inhibitors since they have typical binding modes of the benchmark drug celecoxib. • Design and synthesis of novel series of pyrazolo[3,4- d ]pyrazolo derivatives. • The best hit, 4d with COX-1 IC 50 of 28 µM and COX-2 IC 50 of 23 µM. • 4d adopt similar binding modes to the standard COX-2 inhibitor, celecoxib. • 3a , 3d , 4d and 4f exhibited anti-inflammatory activity that was comparable to celecoxib. In this study, the acid chlorides of pyrazolo[3,4- d ]pyrimidine compounds were prepared and reacted with a number of nucleophiles. The novel compounds were experimentally tested via enzyme assay and they showed cyclooxygenase-2 inhibition activity in the middle micro molar range (4b had a COX-1 IC 50 of 26 µM and a COX-2 IC 50 of 34 µM, 3b had a COX-1 IC 50 of 19 µM and a COX-2 IC 50 of 31 µM, 3a had a COX-2 IC 50 of 42 µM). These compounds were analyzed via docking and were predicted to interact with some of the COX-2 key residues. Our best hit, 4d (COX-1 IC 50 of 28 µM, COX-2 IC 50 of 23 µM), appears to adopt similar binding modes to the standard COX-2 inhibitor, celecoxib, proposing room for possible selectivity. Additionally, the resultant novel compounds were tested in several in vivo assays. Four compounds 3a (COX-2 IC 50 of 42 µM), 3d , 4d and 4f were notable for their anti-inflammatory activity that was comparable to that of the clinically available COX-2 inhibitor celecoxib. Interestingly, they showed greater potency than the famous non-steroidal anti-inflammatory drug, Diclofenac sodium. In summary, these novel pyrazolo[3,4- d ]pyrimidine analogues showed interesting anti-inflammatory activity and could act as a starting point for future drugs. [ABSTRACT FROM AUTHOR]
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- 2019
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3. Discovery of 5-Methylthiazole-Thiazolidinone Conjugates as Potential Anti-Inflammatory Agents: Molecular Target Identification and In Silico Studies
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Michelyne Haroun, Anthi Petrou, Christophe Tratrat, Aggeliki Kolokotroni, Maria Fesatidou, Panagiotis Zagaliotis, Antonis Gavalas, Katharigatta N. Venugopala, Nagaraja Sreeharsha, Anroop B. Nair, Heba Sadek Elsewedy, and Athina Geronikaki
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Molecular Structure ,Cyclooxygenase 2 Inhibitors ,thiazole ,thiazolidinone ,anti-inflammatory activity ,PASS ,COX-1 ,COX-2 ,LOX ,docking ,Anti-Inflammatory Agents, Non-Steroidal ,Organic Chemistry ,Anti-Inflammatory Agents ,Pharmaceutical Science ,Analytical Chemistry ,Molecular Docking Simulation ,Structure-Activity Relationship ,Cyclooxygenase 2 ,Chemistry (miscellaneous) ,Drug Discovery ,Molecular Medicine ,Cyclooxygenase Inhibitors ,Lipoxygenase Inhibitors ,Physical and Theoretical Chemistry - Abstract
A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as the reference drug. Structure–activity relationships revealed that the activity of compounds depends not only on the nature of the substituent but also on its position in the benzene ring. The most active compounds were selected to investigate their possible mechanism of action. COX and LOX activity were determined and found that the title compounds were active only to COX-1 enzymes with an inhibitory effect superior to the reference drug naproxen. As for LOX inhibitory activity, the derivatives failed to show remarkable LOX inhibition. Therefore, COX-1 has been identified as the main molecular target for the anti-inflammatory activity of our compounds. The docking study against COX-1 active site revealed that the residue Arg 120 was found to be responsible for activity. In summary, the 5-thiazol-based thiazolidinone derivatives have been identified as a novel class of selective COX-1 inhibitors.
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- 2022
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4. In silico receptor-based drug design of X,Y-benzenesulfonamide derivatives as selective COX-2 inhibitors.
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Pérez, David J., Sarabia, Orlando, Villanueva-García, Manuel, Pineda-Urbina, Kayim, Ramos-Organillo, Ángel, Gonzalez-Gonzalez, Jorge, Gómez-Sandoval, Zeferino, and Razo-Hernández, Rodrigo Said
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CYCLOOXYGENASE inhibitors , *DRUG design , *QSAR models , *TARGETED drug delivery , *ARTIFICIAL neural networks - Abstract
COX-2 is a widely studied biological target, since its activity is directly related to the inflammation response. The design of COX-2 selective inhibitors is an ongoing topic in drug design. We performed a quantitative structure–activity relationship and docking studies over a series of benzenesulfonamide derivatives on their inhibition towards COX-1 and COX-2, in order to rationalize their selectivity towards COX-2. Constitutional, topological and molecular property descriptors for the QSAR models and molecular docking calculations were employed. The mathematical model highlighted that lipophilic character and size are the most important features for COX-2 inhibition by benzenesulfonamides. A second QSAR model revealed that the dipole moment, the number of hydrogen bond donors and lipophilicity descriptors of benzenesulfonamides are crucial for their binding to COX-1. Moreover, artificial neural networks were employed to improve the prediction power of the COX-1 inhibition QSAR model. In this sense, we proposed new selective potential inhibitors by introducing different halogens into the benzenesulfonamide scaffold, improving their interactions with key residues of COX-2. [ABSTRACT FROM AUTHOR]
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- 2017
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5. Design, synthesis, and evaluation of novel 2-phenylpropionic acid derivatives as dual COX inhibitory-antibacterial agents.
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Karaca Gençer, Hülya, Acar Çevik, Ulviye, Kaya Çavuşoğlu, Betül, Sağlık, Begüm Nurpelin, Levent, Serkan, Atlı, Özlem, Ilgın, Sinem, Özkay, Yusuf, and Kaplancıklı, Zafer Asım
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CARBOXYLIC acid derivatives , *ANTIBACTERIAL agents , *CYCLOOXYGENASE inhibitors , *ENZYME inhibitors , *CHLORAMPHENICOL , *THERAPEUTICS - Abstract
A series of 2-(4-substitutedmethylphenyl)propionic acid derivatives(6a–6m)were synthesized, characterized and evaluated for cyclooxygenase (COX) enzyme inhibitory and antimicrobial activity. Test compounds that exhibited good COX inhibition and antibacterial activity were further screened for their cytotoxicity and genotoxicity. Compounds6hand6lshowed better COX-1 and COX-2 inhibition when compared to ibuprofen. Inhibition potency of these compounds against COX-2 was very close to that of nimesulide. The compounds6d, 6h, 6land6mdisplayed promising antibacterial property when compared to chloramphenicol. However, the compound6lwas emerged as the best dual COX inhibitory-antibacterial agent in this study. The ADME prediction of the compounds revealed that they may have a good pharmacokinetic profile. Docking results of the compounds6hand6lwith COX-1 (PDB ID: 1EQG) also exhibited a strong binding profile. [ABSTRACT FROM PUBLISHER]
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- 2017
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6. Design, synthesis and biological evaluation of novel diphenylthiazole-based cyclooxygenase inhibitors as potential anticancer agents.
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Abdelazeem, Ahmed H., Gouda, Ahmed M., Omar, Hany A., and Tolba, Mai F.
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THIAZOLES , *CYCLOOXYGENASE inhibitors , *ANTINEOPLASTIC agents , *DRUG design , *NONSTEROIDAL anti-inflammatory agents , *CANCER cells - Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications as analgesics and antipyretics. Currently, there is a growing interest in their antitumor activity and their ability to reduce the risk and mortality of several cancers. While several studies revealed the ability of NSAIDs to induce apoptosis and inhibit angiogenesis in cancer cells, their exact anticancer mechanism is not fully understood. However, both cyclooxygenase (COX)-dependent and -independent pathways were reported to have a role. In an attempt to develop new anticancer agents, a series of diphenylthiazole substituted thiazolidinone derivatives was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines. Additionally, the inhibitory activity of the synthesized derivatives against COX enzymes was investigated as a potential mechanism for the anticancer activity. Cytotoxicity assay results showed that compounds 15b and 16b were the most potent anticancer agents with half maximal inhibitory concentrations (IC 50 ) between 8.88 and 19.25 μM against five different human cancer cell lines. Interestingly, COX inhibition assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good COX-2 inhibition comparable to that of celecoxib. Further support to our results were gained by the docking studies which suggested the ability of compound 15b to bind into COX-2 enzyme with low energy scores. Collectively, these results demonstrated the promising activity of the newly designed compounds as leads for subsequent development into potential anticancer agents. [ABSTRACT FROM AUTHOR]
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- 2014
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7. New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5
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Christophe, Tratrat, Michelyne, Haroun, Aliki, Paparisva, Charalmpos, Kamoutsis, Anthi, Petrou, Antonis, Gavalas, Phaedra, Eleftheriou, Athina, Geronikaki, Katharigatta N, Venugopala, Hafedh, Kochkar, and Anroop B, Nair
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Male ,Lipoxygenase ,Anti-Inflammatory Agents ,Carrageenan ,Article ,Mice ,Structure-Activity Relationship ,Naproxen ,Animals ,Edema ,Humans ,Cyclooxygenase Inhibitors ,Lipoxygenase Inhibitors ,anti-inflammatory ,Inflammation ,Arachidonic Acid ,Cyclooxygenase 2 Inhibitors ,COX ,LOX ,Triazoles ,NDGA ,Molecular Docking Simulation ,triazole ,Cyclooxygenase 2 ,docking ,Cyclooxygenase 1 ,Female ,thiazole - Abstract
Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.
- Published
- 2020
8. Synthesis Molecular Docking and Anticancer Activity of Diflunisal Derivatives as Cyclooxygenase Enzyme Inhibitors
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Goknil Pelin Coskun, Fikrettin Şahin, Teodora Djikic, Nezaket Türkel, Taha Bartu Hayal, Kemal Yelekçi, Şükriye Küçükgüzel, Yelekçi, Kemal, [Coskun, Goeknil Pelin] Cumhuriyet Univ, Dept Pharmaceut Chem, Fac Pharm, TR-58140 Sivas, Turkey -- [Djikic, Teodora -- Yelekci, Kemal] Kadir Has Univ, Fac Engn & Nat Sci, Dept Bioinformat & Genet, TR-34083 Istanbul, Turkey -- [Hayal, Taha Bartu -- Turkel, Nezaket -- Sahin, Fikrettin] Yeditepe Univ, Dept Genet & Bioengn, Fac Engn & Architecture, TR-34755 Istanbul, Turkey -- [Kucukguzel, S. Guniz] Marmara Univ, Dept Pharmaceut Chem, Fac Pharm, TR-34668 Istanbul, Turkey, Yelekci, Kemal -- 0000-0002-0052-4926, Turkel, Nezaket -- 0000-0002-4480-7282, Djikic, Teodora -- 0000-0002-6577-7465, Coskun, Goeknil Pelin, Djikic, Teodora, Hayal, Taha Bartu, Turkel, Nezaket, Yelekci, Kemal, Sahin, Fikrettin, and Kucukguzel, S. Guniz
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Male ,Pharmaceutical Science ,Diflunisal ,01 natural sciences ,Analytical Chemistry ,Docking ,Prostate cancer ,0302 clinical medicine ,DESIGN ,Drug Discovery ,chemistry.chemical_classification ,biology ,PROLIFERATION ,Semicarbazides ,PROSTATE-CANCER ,APOPTOSIS ,3. Good health ,Molecular Docking Simulation ,HYDRAZIDE-HYDRAZONES ,CANCER CELL-LINES ,1,2,4-triazole-3-thione ,Anticancer ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,124-triazole-3-thione ,docking ,MCF-7 Cells ,GROWTH ,Molecular Medicine ,Female ,medicine.drug ,EXPRESSION ,Cell Survival ,Antineoplastic Agents ,thiosemicarbazide ,anticancer ,Isozyme ,Article ,lcsh:QD241-441 ,Structure-Activity Relationship ,03 medical and health sciences ,Thiosemicarbazide ,lcsh:Organic chemistry ,Cell Line, Tumor ,medicine ,Humans ,DRUGS ,Cyclooxygenase Inhibitors ,Physical and Theoretical Chemistry ,AGENTS ,Cyclooxygenase 2 Inhibitors ,010405 organic chemistry ,Organic Chemistry ,HEK 293 cells ,COX-2 ,HCT116 Cells ,medicine.disease ,0104 chemical sciences ,HEK293 Cells ,Enzyme ,chemistry ,Docking (molecular) ,Cell culture ,Cancer research ,biology.protein ,Cyclooxygenase ,Drug Screening Assays, Antitumor ,diflunisal - Abstract
WOS: 000445295500134, PubMed ID: 30082676, Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new diflunisal thiosemicarbazides and 1,2,4-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3), colon carcinoma (HCT-116), human breast cancer (T47D), breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically, the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds 6, 10, 15 and 16 did not show cytotoxic effects for the HEK293 cell line. Among them, compounds 15 and 16 demonstrated anticancer activity for the breast cancer cell line T47D, whereas compounds 6 and 10 which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line, consistent with the literature. However, no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound 16 displayed activity against the HCT-116 cell line. Therefore, it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition, molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds 15, and 16. Both 15 and 16 showed high selectivity and affinity toward COX-2 isozyme over COX-1, which is in agreement with the experimental results., Scientific and Technical Research Council of Turkey (TUBITAK) [114S966]; Marie Sklodowska-Curie action, funding scheme: FP7-MC-ITN [608381], This work was supported by The Scientific and Technical Research Council of Turkey (TUBITAK), Research Fund Project Number: 114S966. The authors are grateful to Jurgen Gross from the Institute of Organic Chemistry, University of Heidelberg, for his generous help on obtaining HR-EI/FAB mass spectra of the synthesized compounds. Diflunisal was supplied by Sanovel Pharmaceutical Industry Inc, Istanbul, Turkey. Teodora Djikic kindly acknowledges "Training in Neurodegeneration, Therapeutics, Intervention and Neurorepair" project number 608381 funded by Marie Sklodowska-Curie action, funding scheme: FP7-MC-ITN.
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- 2018
9. New Substituted 5-Benzylideno-2-Adamantylthiazol[3,2-b][1,2,4]Triazol-6(5 H)ones as Possible Anti-Inflammatory Agents.
- Author
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Tratrat, Christophe, Haroun, Michelyne, Paparisva, Aliki, Kamoutsis, Charalmpos, Petrou, Anthi, Gavalas, Antonis, Eleftheriou, Phaedra, Geronikaki, Athina, Venugopala, Katharigatta N., Kochkar, Hafedh, Nair, Anroop B., and Lebreton, Jacques
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ANTI-inflammatory agents , *ARACHIDONIC acid , *CYCLOOXYGENASE inhibitors , *CYCLOOXYGENASE 2 , *SOYBEAN - Abstract
Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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10. Design, synthesis, and evaluation of novel 2-phenylpropionic acid derivatives as dual COX inhibitory-antibacterial agents
- Author
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Begüm Nurpelin Sağlık, Ulviye Acar Çevik, Serkan Levent, Hülya Karaca Gençer, Sinem Ilgın, Betül Kaya Çavuşoğlu, Özlem Atlı, Zafer Asım Kaplancıklı, Yusuf Özkay, Anadolu Üniversitesi, Eczacılık Fakültesi, Mikrobiyoloji Anabilim Dalı, Karaca Gencer, Hülya, Kaya Çavuşoğlu, Betül, Sağlık, Begüm Nurpelin, Atlı Eklioğlu, Özlem, and Kaplancıklı, Zafer Asım
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0301 basic medicine ,Antifungal Agents ,Drug Evaluation, Preclinical ,Pharmacology ,medicine.disease_cause ,01 natural sciences ,Docking ,Mice ,Drug Discovery ,Cytotoxicity ,Cox Inhibition ,Candida ,ADME ,Phenylpropionates ,Chemistry ,General Medicine ,Antimicrobial ,Ibuprofen ,Phenylpropionic Acid ,Anti-Bacterial Agents ,Molecular Docking Simulation ,Biochemistry ,Antibacterial activity ,Research Article ,medicine.drug ,Cell Survival ,Microbial Sensitivity Tests ,Dual Effect ,Gram-Positive Bacteria ,03 medical and health sciences ,Species Specificity ,Gram-Negative Bacteria ,medicine ,Animals ,Cyclooxygenase Inhibitors ,Cyclooxygenase 2 Inhibitors ,Mutagenicity Tests ,010405 organic chemistry ,Spectrum Analysis ,lcsh:RM1-950 ,0104 chemical sciences ,Antibacterial ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Docking (molecular) ,Drug Design ,NIH 3T3 Cells ,Genotoxicity ,Nimesulide - Abstract
WOS: 000399579300016, PubMed ID: 28413890, A series of 2-(4-substitutedmethylphenyl) propionic acid derivatives (6a-6m) were synthesized, characterized and evaluated for cyclooxygenase (COX) enzyme inhibitory and antimicrobial activity. Test compounds that exhibited good COX inhibition and antibacterial activity were further screened for their cytotoxicity and genotoxicity. Compounds 6h and 6l showed better COX-1 and COX-2 inhibition when compared to ibuprofen. Inhibition potency of these compounds against COX-2 was very close to that of nimesulide. The compounds 6d, 6h, 6l and 6m displayed promising antibacterial property when compared to chloramphenicol. However, the compound 6l was emerged as the best dual COX inhibitory-antibacterial agent in this study. The ADME prediction of the compounds revealed that they may have a good pharmacokinetic profile. Docking results of the compounds 6h and 6l with COX-1 (PDB ID: 1EQG) also exhibited a strong binding profile., Anadolu University Scientific Projects Fund [1409S385], This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1409S385.
- Published
- 2017
11. Prospective performance evaluation of selected common virtual screening tools. Case study: Cyclooxygenase (COX) 1 and 2
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Teresa, Kaserer, Veronika, Temml, Zsofia, Kutil, Tomas, Vanek, Premysl, Landa, and Daniela, Schuster
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Models, Molecular ,Drug Evaluation, Preclinical ,AA, arachidonic acid ,PGE2, Prostaglandin E2 ,ECFP4, Extended-connectivity fingerprints 4 ,Docking ,Method comparison ,SEA, Similarity Ensemble Approach ,MNA, multilevel neighborhoods of atoms ,FCFP6, Functional-class fingerprints 6 ,HBD, hydrogen bond donor ,Acc, accuracy ,Tc, Tanimoto coefficient ,Molecular Structure ,R, ring feature ,NI, negative ionizable feature ,XVOL, exclusion volume ,GFA, genetic function approximation ,Cyclooxygenase ,EE, early enrichment ,HIV-1, human immunodeficiency virus 1 ,OEST, ROCS OpenEye shape Tanimoto ,Original Article ,DES, diethylstilbestrol ,TP, true positive hits ,WOMBAT, World of Molecular Bioactivity ,ACE, angiotensin-converting enzyme ,FN, false negative hits ,FP, false positive hits ,KEGG, Kyoto Encyclopedia of Genes and Genomes ,Structure-Activity Relationship ,Shape-based modeling ,C, cation ,TN, true negative hits ,Humans ,Cyclooxygenase Inhibitors ,ROCS, Rapid Overlay of Chemical Structures ,SERMs, selective estrogen receptor modulators ,Pharmacophore modeling ,Ar, aromatic feature ,OE, overall enrichment ,Dose-Response Relationship, Drug ,MB, metal binding feature ,OECS, ROCS OpenEye ComboScore ,DUD, Directory of Useful Decoys ,m. p., melting point ,COX, cyclooxygenase ,H, hydrophobic feature ,Cyclooxygenase 2 ,HBA, hydrogen bond acceptor ,Cyclooxygenase 1 ,PASS, Prediction of Activity Spectra for Substances ,A, anion ,PDB, Protein Databank ,2D similarity-based search - Abstract
Computational methods can be applied in drug development for the identification of novel lead candidates, but also for the prediction of pharmacokinetic properties and potential adverse effects, thereby aiding to prioritize and identify the most promising compounds. In principle, several techniques are available for this purpose, however, which one is the most suitable for a specific research objective still requires further investigation. Within this study, the performance of several programs, representing common virtual screening methods, was compared in a prospective manner. First, we selected top-ranked virtual screening hits from the three methods pharmacophore modeling, shape-based modeling, and docking. For comparison, these hits were then additionally predicted by external pharmacophore- and 2D similarity-based bioactivity profiling tools. Subsequently, the biological activities of the selected hits were assessed in vitro, which allowed for evaluating and comparing the prospective performance of the applied tools. Although all methods performed well, considerable differences were observed concerning hit rates, true positive and true negative hits, and hitlist composition. Our results suggest that a rational selection of the applied method represents a powerful strategy to maximize the success of a research project, tightly linked to its aims. We employed cyclooxygenase as application example, however, the focus of this study lied on highlighting the differences in the virtual screening tool performances and not in the identification of novel COX-inhibitors., Graphical abstract, Highlights • Selected common virtual screening tools were applied in parallel. • Top-ranked hits were investigated with bioactivity profiling tools. • Compounds were tested in vitro for COX activity. • The prospective performance of all applied programs was evaluated and compared.
- Published
- 2014
12. Conformational Characterization of Ipomotaosides and Their Recognition by COX-1 and 2
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Cedric Stephan Graebin, Hugo Verli, Pablo Ricardo Arantes, and Liana G. Sachett
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Magnetic Resonance Spectroscopy ,Stereochemistry ,Pharmaceutical Science ,Molecular Dynamics Simulation ,disaccharides ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,Molecular dynamics ,lcsh:Organic chemistry ,Drug Discovery ,Pyridine ,Carbohydrate Conformation ,resin glycosides ,Molecule ,Cyclooxygenase Inhibitors ,Glycosides ,Ipomoea batatas ,Physical and Theoretical Chemistry ,Aqueous solution ,Plant Extracts ,Organic Chemistry ,COX ,Metadynamics ,Nuclear magnetic resonance spectroscopy ,molecular dynamics ,inflammatory process ,Carbohydrate Sequence ,chemistry ,Cyclooxygenase 2 ,Chemistry (miscellaneous) ,Docking (molecular) ,docking ,Cyclooxygenase 1 ,ipomotaosides ,Molecular Medicine ,Carbohydrate conformation ,Resins, Plant ,Protein Binding - Abstract
The aerial parts of Ipomoea batatas are described herein to produce four new resin glycosides, designated as ipomotaosides A, B, C, and D. Ipomotaoside A was found to present inhibitory activity on both cyclooxygenases. However, the conformational elucidation of these molecules may be difficult due to their high flexibility. In this context, the current work presents a conformational characterization of ipomotaosides A–D in aqueous and nonaqueous solvents. The employed protocol includes metadynamics evaluation and unrestrained molecular dynamics simulations (MD). The obtained data provided structural models for the ipomotaosides in good agreement with previous ROESY distances measured in pyridine. Accordingly, the most abundant conformation of ipomotaoside A in solution was employed in flexible docking studies, providing a structural basis for the compound’s inhibition of COX enzymes. The so-obtained complex supports resin glycosides’ role as original scaffolds for future studies, aiming at structural optimization and development of potential new anti-inflammatory agents.
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- 2014
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13. Structure-based QSAR study on differential inhibition of human prostaglandin endoperoxide H synthase-2 (COX-2) by nonsteroidal anti-inflammatory drugs
- Author
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Pouplana, R., Lozano, J.J., Pérez, C., and Ruiz, J.
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- 2002
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14. Indole Derivatives as Cyclooxygenase Inhibitors: Synthesis, Biological Evaluation and Docking Studies.
- Author
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Bhat, Mashooq Ahmad, Al-Omar, Mohamed A., Raish, Mohammad, Ansari, Mushtaq Ahmad, Abuelizz, Hatem A., Bakheit, Ahmed H., and Naglah, Ahmed M.
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INDOLE derivatives , *HETEROCYCLIC compound derivatives , *CYCLOOXYGENASE inhibitors , *CHEMICAL synthesis , *ANTI-infective agents , *DRUG efficacy , *CHEMICAL reactions - Abstract
A new series of 2-(5-methoxy-2-methyl-1
H -indol-3-yl)-N ′-[(E )-(substituted phenyl) methylidene] acetohydrazide derivatives (S1 –S18 ) were synthesized and evaluated for their anti-inflammatory activity, analgesic activity, ulcerogenic activity, lipid peroxidation, ulcer index and cyclooxygenase expression activities. All the synthesized compounds were in good agreement with spectral and elemental analysis. Three synthesized compounds (S3 ,S7 andS14 ) have shown significant anti-inflammatory activity as compared to the reference drug indomethacin. CompoundS3 was further tested for ulcerogenic index and cyclooxygenase (COX) expression activity. It was selectively inhibiting COX-2 expression and providing the gastric sparing activity. Docking studies have revealed the potential of these compounds to bind with COX-2 enzyme. CompoundS3 formed a hydrogen bond between OH of Tyr 355 and NH2 of Arg 120 with carbonyl group and this hydrogen bond was similar to that formed by indomethacin. This study provides insight for compoundS3 , as a new lead compound as anti-inflammatory agent and selective COX-2 inhibitor. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
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