Bases moleculares da ação anti-inflamatória dos ácidos oleanólico e ursólico sobre as isoformas da ciclo-oxigenase por docking e dinâmica molecular

Magalhães, Wendell Santos; Correa, Celia M.; Alencastro, Ricardo Bicca de; Nagem, Tânus Jorge

doi:10.1590/s0100-40422012000200003

Cited by 6 publications

(8 citation statements)

References 13 publications

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“…The inhibitors selected may have an equivalent affinity in relation to the selected control compounds. The interaction with Ser 353 in Z-814 demonstrates the possibility of a binding activity associated with low IC 50 values [ 28 , 29 , 30 ].…”

Section: Resultsmentioning

confidence: 99%

“…The calculation of binding affinity (∆G) was also performed in order to compare the actual data obtained and the values predicted in silico, which was the same methodology adopted by Santos et al, 2020 [ 14 ], according to Equation (5).

where R (gas constant) is 1.987.10 −3 kcal·mol −1 ·K −1 , the temperature is 310 K for rofecoxib/celecoxib, and K i is 310.10 −9 M for rofecoxib and 340.10 −9 M for celecoxib [ 28 , 32 , 52 ].…”

Section: Methodsmentioning

confidence: 99%

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Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

et al. 2020

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Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side effects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson’s correlation for the construction of quantitative structure–activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (−log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski’s rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

et al. 2020

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“…Because UA has exhibited this feature (multi-targets), it may be considered an advantage over other compounds described in the literature. Verano et al ( 2013 ) has shown that UA 10 mg/kg (i.p) has an antinociceptive effect, so we chose this dose to test its effect orally and have confirmed the antinociceptive and anti-inflammatory effects of UA through inhibitions of the TRPV1 receptor and serotonergic synergism (5-HT); reduced IL-2, IL-6, interferon (IFN)-γ, TNF-α, reactive oxygen species (ROS), phospholipase A2 and NF-κβ release; reduced COX-2 and inducible nitric oxide synthase (iNOS) expression; (Kashyap et al, 2016 ) and favorable interactions for complexes formed with COX-1 and COX-2 (Magalhães et al, 2012 ). Zhang et al ( 2013 ) demonstrated that UA can induce apoptosis of cancer cells by reducing COX-2 expression and Ma et al ( 2014 ) demonstrated that UA reduced COX-2 expression in CCl 4 -treated animals.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive Activity of Borreria verticillata: In vivo and In silico Studies

et al. 2017

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Borreria verticillata (L.) G. Mey. known vassourinha has antibacterial, antimalarial, hepatoprotective, antioxidative, analgesic, and anti-inflammatory, however, its antinociceptive action requires further studies. Aim of the study evaluated the antinociceptive activity of B. verticillata hydroalcoholic extract (EHBv) and ethyl acetate fraction (FAc) by in vivo and in silico studies. In vivo assessment included the paw edema test, writhing test, formalin test and tail flick test. Wistar rats and Swiss mice were divided into 6 groups and given the following treatments oral: 0.9% NaCl control group (CTRL), 10 mg/kg memantine (MEM), 10 mg/kg indomethacin (INDO), 500 mg/kg EHBv (EHBv 500), 25 mg/kg FAc (FAc 25) and 50 mg/kg FAc (FAc 50). EHBv, FAc 25 and 50 treatments exhibited anti-edematous and peripheral antinociceptive effects. For in silico assessment, compounds identified in FAc were subjected to molecular docking with COX-2, GluN1a and GluN2B. Ursolic acid (UA) was the compound with best affinity parameters (binding energy and inhibition constant) for COX-2, GluN1a, GluN2B, and was selected for further analysis with molecular dynamics (MD) simulations. In MD simulations, UA exhibited highly frequent interactions with residues Arg120 and Glu524 in the COX-2 active site and NMDA, whereby it might prevent COX-2 and NMDA receptor activation. Treatment with UA 10 mg/Kg showed peripheral and central antinociceptive effect. The antinociceptive effect of B. verticillata might be predominantly attributed to peripheral actions, including the participation of anti-inflammatory components. Ursolic acid is the main active component and seems to be a promising source of COX-2 inhibitors and NMDA receptor antagonists.

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“…Õ software 27 and molecular docking was performed using AutoDock 4 Õ software 27,28 . Lamarckian genetic algorithms were used as search parameter to find the best conformation assumed by each docking ligand in a total of 50 energy assessment (generations) 27 .…”

Section: In Silico Assaysmentioning

confidence: 99%

“…Lamarckian genetic algorithms were used as search parameter to find the best conformation assumed by each docking ligand in a total of 50 energy assessment (generations) 27 . The enzyme structure was kept rigid and the ligands were kept with maximum allowed flexibility.…”

Section: In Silico Assaysmentioning

confidence: 99%

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

Saito

Lourenço

Dias

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N 0 -substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo [3,4-b]pyridine-4-carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE 2 and TXB 2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.

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Bases moleculares da ação anti-inflamatória dos ácidos oleanólico e ursólico sobre as isoformas da ciclo-oxigenase por docking e dinâmica molecular

Cited by 6 publications

References 13 publications

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

Antinociceptive Activity of Borreria verticillata: In vivo and In silico Studies

Antiplatelet pyrazolopyridines derivatives: pharmacological, biochemical and toxicological characterization

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