Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

Borges, Rosivaldo S.; Palheta, Ivanete Cardoso; Ota, Sirlene S. B.; Morais, Roberto B.; Barros, Valéria A.; Ramos, Ryan da Silva; Silva, Raí C.; Costa, Josivan da Silva; Silva, Carlos Henrique Tomich de Paula da; Campos, Joaquı́n M.; Santos, Cleydson Breno Rodrigues dos

doi:10.3390/molecules24010143

Cited by 17 publications

(16 citation statements)

References 58 publications

(71 reference statements)

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“…Crystallographic complex of rofecoxib with h COX-2 deposited in the PDB under the code 5KIR exhibits the main interactions in the region of monomer B of the protein. Rofecoxib methyl sulfone group binds to the active site of the enzyme, specifically with residues: His90 and Arg513 in the α helix of the hydrophilic part of h COX-2 (chain B) [ 14 , 63 ]. Figure 5 A shows the amino acid residues Phe518, Leu352, Ala527, Ser530, Val349, and Val523 of h COX-2 interacting with rofecoxib [ 14 ].…”

Section: Resultsmentioning

confidence: 99%

“…According to the results ( Table 8 ), the selected compounds did not present any toxicity alert. Results of the pivot compound Rofecoxib, on the other hand, were flagged as “plausible”, since it presented a warning of hepatotoxicity (humans, mice and rats) for derivatives of the furanone group [ 63 ].…”

Section: Resultsmentioning

confidence: 99%

“…The toxicity of the compounds with the best pharmacokinetic profiles was assessed using (DEREK) 10.0.2 Nexus program [ 25 , 40 ]. Deductive Estimation of Risk from Existing Knowledge (DEREK) predicts potential toxicity and toxicophoric groups and also includes the following toxicological parameters: carcinogenicity, mutagenicity, genotoxicity, skin sensitization, teratogenicity, irritation, respiratory sensitization, reproductive toxicity [ 37 , 63 ].…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2020

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“…One way to probe the ability of scoring functions is analyzing the best pose obtained through the program and the conformation of crystallographic ligand [30]. When root-mean-square deviation of atomic positions (RMSD) between them is less than 2 Å, the model achieves satisfactory solutions (conformational search and scoring functions), according to the literature data [31,32,33,34,35,36,37,38,39].…”

Section: Resultsmentioning

confidence: 99%

In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity

et al. 2019

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Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.

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“…Comparison between the crystallographic ligand UK-432097 and the pose (conformation + orientation) predicted by molecular docking for our top-ranked compound can be visualized in Figure 6 and Table 10, which show the poses superimposed with RMSD of 1.58 Å. According to literature, the binding mode prediction using docking should present root mean square deviation (RMSD) value <2.0 Å when superimposed to the crystallographic pose of the ligand [46][47][48]. So, the search parameters were suitable for the docking step and the accuracy of the docking study was corroborated/validated by the crystallographic pose of the agonist into the A 2A AR active site, reinforcing the reliability of our computational protocol to search for new potential leads or hits [23,30].…”

Section: Molecular Docking Studiesmentioning

confidence: 91%

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

et al. 2020

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Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.

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Toward of Safer Phenylbutazone Derivatives by Exploration of Toxicity Mechanism

Cited by 17 publications

References 58 publications

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

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

In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

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