| Přispěvatelé: |
[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, Campos,JM] Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Biosanitary Institute of Granada (Ibs.GRANADA), University of Granada, Granada, Spain. |
| Popis: |
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. |
