Abstract
The anticancer activities of Withaferin-A (Wi-A) and Withanone (Wi-N) from Ashwagandha and Caffeic Acid Phenethyl Ester (CAPE) from honeybee propolis have been well documented. Here, we examined the binding potential of these natural compounds to inhibit the constitutive phosphorylation of epidermal growth factor receptors (EGFRs). Exon 20 insertion mutants of EGFR, which show resistance to various FDA approved drugs and are linked to poor prognosis of lung cancer patients, were the primary focus of this study. Apart from exon 20 insertion mutants, the potential of natural compounds to serve as ATP competitive inhibitors of wildtype protein and other common mutants of EGFR, namely L858R and exon19del, were also examined. The potential of natural compounds was compared to the positive controls such as erlotinib, TAS6417 and poziotinib. Similar to known inhibitors, Wi-A and Wi-N could displace and binds at the ATP orthosteric site of exon19del, L858R and exon20, while CAPE was limited to wildtype EGFR and exon 20 insertion mutants only. Moreover, the binding free energy of the natural drugs against EGFRs was also comparable to the positive controls. This computational study suggests that Wi-A and Wi-N have potential against multiple mutated EGFRs, warranting further in vitro and in vivo experiments.
Highlights
Lung cancer is a leading cause of death worldwide [1]
The second mutant was exon 21 point mutation, in which any amino acid ranging from 824 to 875 could be mutated; for this study, L858R was chosen as it was most frequent [51]. The structures of these mutants were created by introducing mutations in wildtype epidermal growth factor receptors (EGFRs)–ATP complex followed by molecular dynamic (MD) simulation
There are multiple synthetic drugs which are in advanced stage of clinical trials and some are approved as EGFR inhibitor such as gefitinib, erlotinib, poziotinib, osimertinib, lapatinib and many more [64,65,66,67]
Summary
Lung cancer is a leading cause of death worldwide [1]. It is primarily categorized into two subtypes-small cell lung cancer (SCLC) that accounts for 15% of the lung cancer cases and non-small cell lung cancer (NSCLC) that accounts for the remaining 85% [2,3,4,5]. The most common cause of NSCLC reported in several studies is the constitutive activation of EGFR (Epidermal Growth Factor Receptor) [6,7]. EGFR is a 170-kD transmembrane glycoprotein that promotes cell proliferation. It has an extracellular domain for ligand binding, a transmembrane (TM) region and intracellular tyrosine kinase and regulatory domains [8,9]. The binding of the EGFR receptor to its ligand (EGF) causes its homo-dimerization that stimulates its intrinsic tyrosine kinase activity, causing autophosphorylation of the receptor and phosphorylation of various substrates in the cell [10]. The vast majority of activating mutations in the EGFR gene have been reported as key-drivers in NSCLC.
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