Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

Abstract

A pharmacophore model has been developed using diverse classes of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors useful in the treatment of human tumours. Among the top 10 generated hypotheses, the second hypothesis, with one hydrogen bond acceptor, one ring aromatic and three hydrophobic features, was found to be the best on the basis of Cat Scramble validation as well as test set prediction (r(training) = 0.89, r(test) = 0.82). The model also maps well to the external test set molecules as well as clinically active molecules and corroborates the docking studies. Finally, 10 hits were identified as potential leads after virtual screening of ZINC database for EGFR TK inhibition. The study may facilitate the designing and discovery of novel EGFR TK inhibitors.

Computer-aided identification of EGFR tyrosine kinase inhibitors using ginsenosides from Panax ginseng

“…Among 11 features available, the hydrogen bond acceptor (HBA), hydrogen bond donors (HBD), hydrogen bond acceptor lipid (HBA lipid), ring aromatic (RA), and hydrophobic (HY) features were selected to develop the pharmacophore model. Similar pharmacophore modeling work [33] has been carried out previously, suggesting that HBA, RA, and HY features are important for the EGFR TK active site. The pharmacophore model was generated with DS 2.5 using default parameters.…”

“…A total of 36 EGFR TK inhibitors with experimental inhibitory activity (IC 50 ) values were collected from the literature [33] for use in this study. These compounds, demonstrating a wide range of IC 50 values from 0.38 nM to 3300 nM, were used for pharmacophore model generation.…”

“…Several chemical substances were identified for EGFR tyrosine kinase inhibitors based on pharmacophore model, virtual screening, and molecular docking methods [13,[31][32][33][34]. In order to identify novel lead molecules with pharmacophore features were important task in medicinal plant.…”

Molecular docking approach to identify potential anticancer compounds from Begonia (Begonia sp)

“…Epidermal Growth Factor Receptor (EGFR) is a cellular transmembrane glycoprotein that activates tyrosine kinase domain through dimerization to regulate multiple key functions such as cancer cell differentiation, proliferation, survival, and apoptosis. It is highly expressed in a wide variety of human tumors, especially breast, colon, cervical and bladder cancer [6]. Targeting this receptor in molecular docking process is a good strategy in anticancer drug discovery campaign.…”

Triple-layered QSAR studies on substituted 1,2,4-trioxanes as potential antimalarial agents: superiority of the quantitative pharmacophore-based alignment over common substructure-based alignment

“…Therefore, considering the importance of artemisinin and its analogues as a potent class of antimalarial drugs effective against the multidrug-resistant P. falciparum strains, and the unavailability of the exact target for this class of molecule [10], we have earlier reported the Discovery Studio (DS)-based [11] quantitative pharmacophore model utilizing this class of molecules [12]. DS-based pharmacophore models are computationally intensive, as they consider many conformations ( 255) of each molecule to generate the QSAR equations [13]; they give the minimum essential structural requirements for activity in terms of favourable regions, and do not give any information about features that diminish biological activity. The successful application of comparative field molecular analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques to understand the effect of contrasting structural requirements in 3D chemical space has been reported by many research groups in the recent past [14,15].…”