1. Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches
- Author
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Sebastião Gomes Silva, Joaquín M. Campos, Pedro H F Araújo, Cleydson B. R. Santos, José M Espejo-Román, Ryan da Silva Ramos, Williams Jorge da Cruz Macêdo, Lúcio R de Lima, Jorddy Neves Cruz, Elenilze F B Ferreira, [Araújo,PHF, Ferreira,EFB, Macedo,WJC, Santos,CBR] Graduate Program in Innovation Pharmaceutical, Federal University of Amapá, Amapá-AP, Brazil. [Araújo,PHF, Ramos,RS, da Cruz,JN, de Lima,LR, Santos,CBR] Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá-AP, Brazil. [Silva,SG] Campus Abaetetuba, Universidade Federal do Para, Abaetetuba, Pará, Brazil. [Ferreira,EFB] Laboratory of Organic Chemistry and Biochemistry, University of State of Amapá, Macapá-AP, Brazil. [Macedo,WJC, Santos,CBR] Laboratory of Molecular Modeling and Simulation System, Federal Rural University of Amazônia, Capanema, Pará-PA, Brazil. [Espejo-Román,JM, and Campos,JM] Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Biosanitary Institute of Granada (Ibs.GRANADA), University of Granada, Granada, Spain.
- Subjects
Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Protein Binding [Medical Subject Headings] ,Molecular model ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Quantitative Structure-Activity Relationship ,Inhibidores de la ciclooxigenasa 2 ,Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Structure-Activity Relationship::Quantitative Structure-Activity Relationship [Medical Subject Headings] ,01 natural sciences ,In vivo tests ,Analytical Chemistry ,Madin Darby Canine Kidney Cells ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Lactones ,Information Science::Information Science::Computing Methodologies::Software [Medical Subject Headings] ,Drug Discovery ,Organisms::Eukaryota::Animals [Medical Subject Headings] ,Sulfones ,0303 health sciences ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Carnivora::Canidae::Dogs [Medical Subject Headings] ,Molecular Structure ,Chemistry ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery::Drug Evaluation, Preclinical [Medical Subject Headings] ,Molecular Docking Simulation ,Anatomy::Cells::Epithelial Cells::Caco-2 Cells [Medical Subject Headings] ,in silico ,Chemistry (miscellaneous) ,Lipinski's rule of five ,Molecular Medicine ,Regression Analysis ,Pharmacophore ,Protein Binding ,Quantitative structure–activity relationship ,In silico ,030303 biophysics ,Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Inhibitory Concentration 50 [Medical Subject Headings] ,Computational biology ,Diseño de fármacos ,Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Inflammatory Agents::Anti-Inflammatory Agents, Non-Steroidal::Cyclooxygenase Inhibitors::Cyclooxygenase 2 Inhibitors [Medical Subject Headings] ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular::Molecular Docking Simulation [Medical Subject Headings] ,Article ,Permeability ,COX-2 inhibitors ,lcsh:QD241-441 ,03 medical and health sciences ,Inhibitory Concentration 50 ,Phenomena and Processes::Chemical Phenomena::Molecular Structure [Medical Subject Headings] ,Dogs ,lcsh:Organic chemistry ,Animals ,Humans ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery::Drug Design [Medical Subject Headings] ,Physical and Theoretical Chemistry ,Chemicals and Drugs::Organic Chemicals::Sulfur Compounds::Sulfones [Medical Subject Headings] ,Inflammation ,Virtual screening ,Simulación por computador ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Regression Analysis [Medical Subject Headings] ,Binding Sites ,Cyclooxygenase 2 Inhibitors ,molecular modeling ,Organic Chemistry ,Information Science::Information Science::Computing Methodologies::Computer Simulation [Medical Subject Headings] ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Molecular Structure::Binding Sites [Medical Subject Headings] ,Zinc database ,Phenomena and Processes::Chemical Phenomena::Permeability [Medical Subject Headings] ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Chemicals and Drugs::Organic Chemicals::Lactones [Medical Subject Headings] ,Celecoxib ,Anatomy::Cells::Cells, Cultured::Cell Line::Madin Darby Canine Kidney Cells [Medical Subject Headings] ,Caco-2 Cells ,Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings] ,Software - Abstract
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&rsquo, s correlation for the construction of quantitative structure&ndash, 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 (&minus, log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski&rsquo, 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.
- Published
- 2020