INSILICO DISCOVERY OF HUMAN AURORA B KINASE INHIBITORS BY MOLECULAR DOCKING, PHARMACOPHORE VALIDATION AND ADMET STUDIES
DOI:
https://doi.org/10.22159/ajpcr.2017.v10i2.14974Abstract
Objectives: To predict the anticancer potentiality of some newly designed azaindole derivatives gainst human Aurora B kinase and to identify the critical features important for their activity.
Methods: Initially, the derivatives of azaindoles, (Z)-2-(oxo-1 H-pyrrolo [2,3-b] pyridine-3 (2H)-ylidene)-N-(p-substituted) hydrazine carbothioamide (scaffold A), (E)-3-((E)-substituted benzylidene hydrazono)-1H-pyrrolo[2,3-b]pyridine-2(3H)-one (scaffold B), and 1-(2-substituted acetyl)-1H- pyrrolo [2,3-b]pyridine-2,3-dione are synthesized and sketched using ACD/ChemSketch (12.0). With the 3D converted compounds, docking into the active site of the retrieved protein Aurora B kinase is carried out using LibDock module of discovery studio (DS). Further absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, ligand, and structure-based pharmacophore modeling are applied using DS.
Results: Through docking and pharmacophore studies, it is revealed that compound C13 (N-{(Z)-2-[4-(dimethylamino)phenyl]ethenyl}-1H- pyrrolo[2,3-b]pyridine-3-carboxamide) shows the highest binding affinity and good pharmacophoric features with acceptable fit values of both ligand and structure-based pharmacophore models. Furthermore, the calculated ADMET properties are reliable.
Conclusion: These studies suggest that the compound C13 (N-{(Z)-2-[4-(dimethylamino)phenyl]ethenyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxamide)
may act as a potent target in the anticancer therapy.
Keywords: Aneuploidy, Aurora B kinase, Azaindole, Cancer, Cell cycle, Genome stability.
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