Virtual Screening for Finding Novel COX-2 Inhibitors as Antitumor Agents



Zohreh S Badieyan1, 4, Seyed Adel Moallem*, 2, 3, 4, Soghra Mehri4, Shabnam Shahsavand4, Farzin Hadizadeh*, 1, 4
1 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Pharmaceutical Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
3 Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
4 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran


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© Badieyan et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http: //creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to these authors at the Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, and School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Tel: 0098-511-8823252; Fax: 0098-511-8823251; E-mails: moallem@mums.ac.ir; hadizadehf@mums.ac.ir


Abstract

The cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid resulting in the release of metabolites that induce pain and inflammatory responses. Recent studies have shown that strong COX-2 expression is highly correlated with increased tumor risk. Therefore, the development of potent COX-2 inhibitors to relieve pain and treat cancers requires further investigation. We used virtual screening to find three COX-2 inhibitors (Phar-95239, T0511-4424 and Zu- 4280011) from a huge zinc database containing 2000000 compounds. The effects of the compounds on COX-2 were compared to those on COX-1 using a colorimetric COX (ovine) screening assay kit. The selectivity index, the ratio of IC50 for COX-1 inhibition to that of COX-2, calculated were MTT assay was used to evaluate the cytotoxic activity of the compounds using different dilutions. The IC50 values were calculated. Based on the results of the MTT assay, the IC50 values for compounds Phar-95239, T0511-4424 and Zu-4280011 were 178.52, 143 and 97.61 µM, respectively, and the selectivity indices of the compounds were 11.36, 12.20 and 20.03, respectively. These results indicated a relationship between the selectivity index and anticancer activity. Zu-4280011 displayed the highest selectivity index and the best results in the MTT assay among selected componds.

Keywords: Cyclooxygenase, MTT, Selectivity index, Virtual Screening, Zinc database.