alexa Abstract | THE DESIGN AND OPTIMISATION OF NOVEL STRUCTURES CAPABLE OF EPIDERMAL GROWTH FACTOR INHIBITION FOR THE MANAGEMENT OF NEOPLASTIC DISEASE


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Abstract

Overexpression of Epidermal Growth Factor Receptors (EGFRs) due to gene amplification has been associated with the development of tumours of epithelial origin, including breast, lung, colon and ovarian. EGFRs are consequently targets for the design of antagonist molecules with the potential of solid tumour management. 2- O-caffeoyl tartaric acid, 2-O-feruloyl tartaric acid, Emetine and Rosmaricine are molecules for which there is evidence, from Chinese Pharmacopeia, of their ability to antagonise EGFR. These molecules were used as templates in the de novo design of novel EGFR inhibitors. Protein databank crystallographic deposition 2ITY, describing the holo-gefitinib: EGFR complex, was used to define the pharmacophoric space available for novel molecular growth. 2-O-caffeoyl tartaric acid, 2-O-feruloyl tartaric acid, Emetine and Rosmaricine were successively docked into the EGFR ligand binding pocket (LBP) and conformational analysis performed. The optimal conformer for each molecule became the scaffold onto which novel moieties were computationally introduced at loci considered non-critical to binding using the GROW module of LigBuilder® v1.2. 66, 16, 17 and 55 molecules were designed from 2-O-caffeoyl tartaric acid, 2-O-feruloyl tartaric acid, Emetine and Rosmaricine scaffolds respectively after a larger cohort (n= 1770) was assessed for Lipinski Rule compliance. These molecules were classified according to pharmacophoric similarity, physiochemical parameters and ligand binding affinity. Their binding affinity (pKd), ranged between 10 and 5.76 compared to 6.05 for gefitinib. The highest affinity Lipinski Rule compliant molecules are being suggested for further optimisation, synthesis and in vitro validation. This in silico study validated the utility of the selected lead scaffolds in the design of novel EGFR inhibitors.

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Author(s): Marie Claire Farrugia*, Claire Shoemake and Mary Ann Sant Fournier

Keywords

EGFR, 2-O-caffeoyl tartaric acid, 2-O-feruloyl tartaric acid, Emetine, Rosmaricine, Pharmacy

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