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

Rozires P Leão; Josiane V Cruz; Glauber V da Costa; Jorddy N Cruz; Elenilze F B Ferreira; Raí C Silva; Lúcio R de Lima; Rosivaldo S Borges; Gabriela B Dos Santos; Cleydson B R Santos

doi:10.3390/ph13090209

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

Pharmaceuticals (Basel). 2020 Aug 26;13(9):209. doi: 10.3390/ph13090209.

Authors

Rozires P Leão^{1

2}, Josiane V Cruz², Glauber V da Costa², Jorddy N Cruz², Elenilze F B Ferreira^{2

3}, Raí C Silva^{1

2

4}, Lúcio R de Lima^{1

2}, Rosivaldo S Borges¹, Gabriela B Dos Santos⁵, Cleydson B R Santos^{1

2}

Affiliations

¹ Graduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute, Federal University of Pará, Belém 66075-110, PA, Brazil.
² Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá 68902-280, AP, Brazil..
³ Laboratory of Organic Chemistry and Biochemistry, University of State of Amapá, Macapá 68900-070, AP, Brazil.
⁴ Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto 14090-901, SP, Brazil.
⁵ Institute of Collective Health, Federal University of Western Pará, Santarém 68040-255, PA, Brazil.

Abstract

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.

Keywords: anti-inflammatory; bioinformatics; cyclooxygenase-2; rofecoxib.