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Computational modeling of novel quinazoline derivatives as potent epidermal growth factor receptor inhibitors.

ABSTRACT: QSAR modelling on Thirty (34) novel quinazoline derivatives (EGFRWT inhibitors) as non-small cell lung cancer (NSCLC) agents was performed to develop a model with good predictive power that can predict the activities of newly designed compounds that have not been synthesised. The EGFRWT inhibitors were optimized at B3LYP/6-31G* level of theory using Density Functional Theory (DFT) method. Multi-Linear Regression using Genetic Function Approximation (GFA) method was adopted in building the models. The best one among the models built was selected and reported because it was found to have passed the minimum requirement for the assessment of QSAR models with the following assessment parameters: R2 of 0.965901, R2 adj of 0.893733, Qcv 2 of 0.940744, R2 test of 0.818991 and LOF of 0.076739. The high predicted power, reliability, robustness of the reported model was verified further by subjecting it to other assessments such VIF, Y-scrambling test and applicability domain. Molecular docking was also employed to elucidate the binding mode of some selected EGFRWT inhibitors against EGFR receptor (4ZAU) and found that molecule 17 have the highest binding affinity of -9.5 kcal/mol. It was observed that the ligand interacted with the receptor via hydrogen bond, hydrophobic bond, halogen bond, electrostatic bond and others which might me the reason why it has the highest binding affinity. Also, the ADME properties of these selected molecules were predicted and only one molecule (34) was found not orally bioavailable because it violated more than the permissible limit set by Lipinski's rule of five filters. This findings proposed a guidance for designing new potents EGFRWT inhibitors against their target enzyme.

SUBMITTER: Ibrahim MT

PROVIDER: S-EPMC7013192 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Computational modeling of novel quinazoline derivatives as potent epidermal growth factor receptor inhibitors.

Ibrahim Muhammad Tukur MT Uzairu Adamu A Uba Sani S Shallangwa Gideon Adamu GA

Heliyon 20200207 2

QSAR modelling on Thirty (34) novel quinazoline derivatives (EGFR<sup>WT</sup> inhibitors) as non-small cell lung cancer (NSCLC) agents was performed to develop a model with good predictive power that can predict the activities of newly designed compounds that have not been synthesised. The EGFR<sup>WT</sup> inhibitors were optimized at B3LYP/6-31G* level of theory using Density Functional Theory (DFT) method. Multi-Linear Regression using Genetic Function Approximation (GFA) method was adopted ...[more]

PMID: 32072038

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Project description:Oesophageal squamous cell carcinomas and oesophageal adenocarcinomas show distinct patterns of ErbB expression and dimers. The functional effects of specific ErbB homodimers or heterodimers on oesophageal (cancer) cell behaviour, particularly invasion during early carcinogenesis, remain unknown. Here, a new cellular model system for controlled activation of epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) and EGFR-HER2 or HER2-human epidermal growth factor receptor 3 (HER3) homodimers and heterodimers was studied in non-neoplastic squamous oesophageal epithelial Het-1A cells. EGFR, HER2 and HER3 intracellular domains (ICDs) were fused to dimerization domains (DmrA/DmrA and DmrC), and transduced into Het-1A cells lacking ErbB expression. Dimerization of EGFR, HER2 or EGFR-HER2 and HER2-HER3 ICDs was induced by synthetic ligands (A/A or A/C dimerizers). This was accompanied by phosphorylation of the respective EGFR, HER2 and HER3 ICDs and activation of distinct downstream signalling pathways, such as phospholipase C?1, Akt, STAT and Src family kinases. Phenotypically, ErbB dimers caused cell rounding and non-apoptotic blebbing, specifically in EGFR-HER2 and HER2-HER3 heterodimer cells. In a Transwell assay, cell migration velocity was elevated in HER2 dimer cells as compared with empty vector cells. In addition, HER2 dimer cells showed in increased cell invasion, reaching significance for induced HER2-HER3 heterodimers (P?=?0.015). Importantly, in three-dimensional organotypic cultures, empty vector cells grew as a superficial cell layer, resembling oesophageal squamous epithelium. In contrast, induced HER2 homodimer cells were highly invasive into the matrix and formed cell clusters. This was associated with partial loss of cytokeratin 7 (when HER2 homodimers were modelled) and p63 (when EGFR-HER2 heterodimers were modelled), which suggests a change or loss of squamous cell differentiation. Controlled activation of specific EGFR, HER2 and HER3 homodimers and heterodimers caused oesophageal squamous epithelial cell migration and/or invasion, especially in a three-dimensional microenvironment, thereby functionally identifying ErbB homodimers and heterodimers as important drivers of oesophageal carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Computational modeling of novel quinazoline derivatives as potent epidermal growth factor receptor inhibitors.

Publications

Computational modeling of novel quinazoline derivatives as potent epidermal growth factor receptor inhibitors.

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