Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches
Pedro H. F. Araújo,
Ryan S. Ramos,
Jorddy N. da Cruz,
Sebastião G. Silva,
Elenilze F. B. Ferreira,
Lúcio R. de Lima,
Williams J. C. Macêdo,
José M. Espejo-Román,
Joaquín M. Campos,
Cleydson B. R. Santos
Affiliations
Pedro H. F. Araújo
Graduate Program in Innovation Pharmaceutical, Federal University of Amapá, 68903-419 Amapá-AP, Brazil
Ryan S. Ramos
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Jorddy N. da Cruz
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Sebastião G. Silva
Campus Abaetetuba, Universidade Federal do Para, Ramal Manoel de Abreu, s/n-Mutirão, Abaetetuba, 68440-000 Pará, Brazil
Elenilze F. B. Ferreira
Graduate Program in Innovation Pharmaceutical, Federal University of Amapá, 68903-419 Amapá-AP, Brazil
Lúcio R. de Lima
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Williams J. C. Macêdo
Graduate Program in Innovation Pharmaceutical, Federal University of Amapá, 68903-419 Amapá-AP, Brazil
José M. Espejo-Román
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Biosanitary Institute of Granada (Ibs.GRANADA), Campus of Cartuja s/n, University of Granada, 18071 Granada, Spain
Joaquín M. Campos
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Biosanitary Institute of Granada (Ibs.GRANADA), Campus of Cartuja s/n, University of Granada, 18071 Granada, Spain
Cleydson B. R. Santos
Graduate Program in Innovation Pharmaceutical, Federal University of Amapá, 68903-419 Amapá-AP, Brazil
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.
