A crystallographic and theoretical study of an (E)-2-Hydroxyiminoethanone derivative: prediction of cyclooxygenase inhibition selectivity of stilbenoids by MM-PBSA and the role of atomic charge

Balef, S. S. H., Chippindale, A. M. ORCID: https://orcid.org/0000-0002-5918-8701 and Irannejad, H. (2019) A crystallographic and theoretical study of an (E)-2-Hydroxyiminoethanone derivative: prediction of cyclooxygenase inhibition selectivity of stilbenoids by MM-PBSA and the role of atomic charge. Journal of Biomolecular Structure and Dynamics, 37 (6). pp. 1555-1566. ISSN 0739-1102 doi: 10.1080/07391102.2018.1462256

Abstract/Summary

We recently reported that a hydroxyiminoethanone derivative behaves as a highly selective COX-1 inhibitor (COX-1 SI= 833), and also an interesting scaffold with unique characteristics. In the current study, a comprehensive crystallographic and computational study was performed to elucidate its conformational stability and pharmacological activity. Its conformational energy was studied at the B3LYP/6-311G** level of theory and compared to the single-crystal X-ray data. In addition, computational studies of three structurally different stilbenoid derivatives used as selective COX-1 or COX-2 inhibitors were performed to predict their COX selectivity potentials. Flexible docking was performed for all compounds at the active site of both COX-1 and COX-2 enzymes by considering some of the key residues as flexible during the docking operation. In the next step, molecular dynamic simulation and binding free energy calculations were performed by MM-PBSA. Final results were found to be highly dependent on the atomic charges of the inhibitors and the choice of force field used to calculate the atomic charges. The binding conformation of the hydroxyiminoethanone derivative is highly correlated with the type of COX isoform inhibited. Our predictive approach can truly predict the cyclooxygenase inhibition selectivity of stilbenoid inhibitors.

Item Type	Article
URI	https://reading-pure-test.eprints-hosting.org/id/eprint/77821
Identification Number/DOI	10.1080/07391102.2018.1462256
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > Department of Chemistry
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