Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches F. Araújo, Pedro H. Espejo Román, José Manuel In silico COX-2 inhibitors Molecular modeling Conceptualization, P.H.F.A., W.J.C.M. and C.B.R.S.; methodology, P.H.F.A. and C.B.R.S..; software, R.S.R. and E.F.B.F.; validation, P.H.F.A., S.G.S., L.R.d.L., J.M.E.-R. and C.B.R.S,; formal analysis, P.H.F.A., R.S.R., J.N.d.C., J.M.C. and C.B.R.S.; investigation, P.H.F.A., R.S.R. and C.B.R.S..; resources, P.H.F.A., W.J.C.M., R.S.R. and C.B.R.S.; data curation, P.H.F.A., R.S.R. and C.B.R.S.; writing—original draft preparation, P.H.F.A. and C.B.R.S.; writing—review and editing, J.M.C and J.N.d.C.; visualization, P.H.F.A.; supervision, C.B.R.S.; project administration, C.B.R.S.; funding acquisition, J.M.C., C.B.R.S., P.H.F.A.,W.J.C.M and E.F.B.F. All authors have read and agreed to the published version of the manuscript. Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side e ects 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. 2020-12-16T09:33:07Z 2020-12-16T09:33:07Z 2020-09-12 journal article Araújo, P. H., Ramos, R. S., da Cruz, J. N., Silva, S. G., Ferreira, E. F., de Lima, L. R., ... & Santos, C. B. (2020). Identification of potential COX-2 inhibitors for the treatment of inflammatory diseases using molecular modeling approaches. Molecules, 25(18), 4183. [doi:10.3390/molecules25184183] http://hdl.handle.net/10481/64945 10.3390/molecules25184183 eng http://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España Mdpi