Title

Virtual screening for novel COX-2 inhibitors using the ZINC database

Authors

Kotaprolu Naga Sudha^{1, *}, Mohammed Shakira¹, Paturi Prasanthi¹, Nalla Sarika¹, Ch Narasimha Kumar² and Padavala Ajay Babu²

Affiliation

¹Department of Microbiology, Sir C. R Reddy College for Women, Vatluru, Eluru 534125, India; ²ProGene Biosciences, Institute of Bioinformatics and Research Centre, 103, Bharat Towers, Dwaraka Nagar, Visakhapatnam 530016, India

Email

subha_vsk29@yahoo.co.in; * Corresponding author

Article Type

Hypothesis

Date

received March 20, 2008; revised April 24, 2008; accepted April 25, 2008; published May 13, 2008

Abstract

Cyclooxygenase-2 (COX-2) enzyme binds to arachidonic acid and releases metabolites that are used to induce pain and inflammation. COX-2 selective inhibitors such as celecoxib, rofecoxib and valdecoxib are currently used to reduce inflammatory response. However, they lack anti-thrombotic activity and hence lead to cardiovascular and renal liabilities apart from gastrointestinal irritation. Therefore, there is still a need to develop more potent COX-2 inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains 4.6 million small molecule compounds) using the eHiTS (electronic High Throughput Screening) software tool against the COX-2 protein. The strategy employed can be conveniently split into two categories, viz. screening and docking, respectively. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 6COX bound ligand SC-558. The analysis resulted in 1042 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified two molecules ZINC00663976 (eHITS score of -7.135 kcal/mol) and ZINC02062094 (eHITS score of -7.242 kcal/mol) from the ZINC database. Their energy scores are better than the 6COX bound co-crystallized ligand SC-558 with an eHiTS score of -6.559 kcal/mol. Both the ligands were docked within the binding pocket forming interactions with Leu352, Phe518, Met522, Val523, Ala527 and Ser353. Visual inspection suggested similar orientation and binding mode for ZINC02062094 with SC-558 ligand. The NH group of the ligand formed hydrogen bond interactions with the backbone NH of Ala527.

Keywords

cyclooxygenase; ZINC database; virtual screening; e-HiTS

Citation

Sudha et al., Bioinformation 2(8): 325-329 (2008)

Edited by

P. Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.