Structural signature of the G719S-T790M double mutation in the EGFR kinase domain and its response to inhibitors (original) (raw)
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Epidermal growth factor receptor (EGFR) is an intensively focused target for anti-tumor compounds used in non-small cell lung cancer (NSCLC) therapy. Compared to the classical activating mutations, there are still many uncommon EGFR mutations associated with poorer responses to EGFR inhibitors. A detailed understanding of the molecular basis for multiple EGFR mutants exhibiting diverse responses to inhibitors is of critical importance for related drug development. Herein, we explored the molecular determinants contributing to the distinct responses of EGFR with a single rare mutation (G719S) or combined mutations (G719S/L858R and G719S/l861Q) to Gefitinib (IRE). Our results indicated that interactions, formed within the tetrad of residues S768 (in the αC-helix), D770 (in the αC-β4 loop), Y827 (in the αE-helix), and R831 (in the catalytic loop), play an important role in the stability of αC-helix and the maintenance of K745–E762 salt bridge in the absence of IRE, which are weakened i...
Development of triple mutant T790M/C797S allosteric EGFR inhibitors: a computational approach
Journal of Biomolecular Structure and Dynamics, 2020
The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. EGFR inhibitors binding allosterically to C797S mutant EGFR enzyme have been developed. Here, database building, library screening performing R-group enumeration and scaffold hopping technique for increasing the EGFR binding affinity of compounds have been carried out. Virtual screening was performed subjecting to HTVS, SP and XP docking protocol along with its relative binding free energy calculations. Molecular docking studies provided the information about binding pockets and interactions of molecules on mutant (PDB: 5D41) as well as wild type (PDB: 4I23) EGFR enzyme. This was supported with ADMET and molecular simulation studies. On the basis of glide score and protein-ligand interactions, highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. The virtually screened molecules can act as potential EGFR inhibitors in the management of drug resistance.
Cells, 2019
The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely understood. One challenge is that the many structure fragments stored at the PDB only provide a partial view because full-length proteins are flexible entities and dynamics play a key role in their functionality. Another challenge is the shortage of high-resolution data on functionally important higher-order complexes. Still, the interest in the structure/function relationships of EGFR remains unabated because of the crucial role played by oncogenic EGFR mutants in driving non-small cell lung cancer (NSCLC). Despite targeted therapies against EGFR setting a milestone in the treatment of this disease, ubiquitous drug resistance inevitably emerges after one year or so of treatment. The magnit...
Molecular Cancer Therapeutics, 2012
The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine kinase inhibitors in patients with non–small cell lung cancer. In this study, we have conducted molecular dynamics simulations over several microseconds for wild-type and L858R mutant forms of EGFR in the ligand-free state. Close inspection of the conformations and interactions within the binding pocket reveals, converse to the wild type, that the mutant EGFR prefers to bind gefitinib, a targeted anticancer drug, rather than ATP, offering an explanation for why gefitinib is more effective in patients with EGFR mutations than those without. Mol Cancer Ther; 11(11); 2394–400. ©2012 AACR.
Frontiers in Molecular Biosciences
The emergence of drug resistance may increase the death rates in advanced non-small cell lung cancer (NSCLC) patients. The resistance of erlotinib, the effective first-line antitumor drug for NSCLC with the L858R mutation of epidermal growth factor receptor (EGFR), happens after the T790M mutation of EGFR, because this mutation causes the binding of adenosine triphosphate (ATP) to EGFR more favorable than erlotinib. However, the mechanism of the enhancement of the binding affinity of ATP to EGFR, which is of paramount importance for the development of new inhibitors, is still unclear. In this work, to explore the detailed mechanism of the drug resistance due to the T790M mutation, molecular dynamics simulations and absolute binding free energy calculations have been performed. The results show that the binding affinity of ATP with respect to the L858R/T790M mutant is higher compared with the L858R mutant, in good agreement with experiments. Further analysis demonstrates that the T79...
The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine kinase inhibitors in patients with non–small cell lung cancer. In this study, we have conducted molecular dynamics simulations over several microseconds for wild-type and L858R mutant forms of EGFR in the ligand-free state. Close inspection of the conformations and interactions within the binding pocket reveals, converse to the wild type, that the mutant EGFR prefers to bind gefitinib, a targeted anticancer drug, rather than ATP, offering an explanation for why gefitinib is more effective in patients with EGFR mutations than those without. Mol Cancer Ther; 11(11); 2394–400. Ó2012 AACR.
Journal of The Royal Society Interface, 2011
The epidermal growth factor receptor (EGFR) is a major target for drugs in treating lung carcinoma. Mutations in the tyrosine kinase domain of EGFR commonly arise in human cancers, which can cause drug sensitivity or resistance by influencing the relative strengths of drug and ATP-binding. In this study, we investigate the binding affinities of two tyrosine kinase inhibitors—AEE788 and Gefitinib—to EGFR using molecular dynamics simulation. The interactions between these inhibitors and the EGFR kinase domain are analysed using multiple short (ensemble) simulations and the molecular mechanics/Poisson–Boltzmann solvent area (MM/PBSA) method. Here, we show that ensemble simulations correctly rank the binding affinities for these systems: we report the successful ranking of each drug binding to a variety of EGFR sequences and of the two drugs binding to a given sequence, using petascale computing resources, within a few days.
International Journal of Molecular Sciences, 2020
Non-small cell lung cancer (NSCLC) represents a difficult condition to treat, due to epidermal growth factor receptor (EGFR) kinase domain mutations, which lead to ligand-independent phosphorylation. Deletion of five amino acids (ELREA) in exon 19 and mutational change from leucine to arginine at position 858 (L858R) are responsible for tyrosine kinase domain aberrant activation. These two common types of EGFR-mutated forms are clinically associated with high response with Tyrosine Kinase Inhibitors (TKI); however, the secondary T790M mutation within the Tyrosine Kinase Domain (TKD) determines a resistance to these EGFR-TKIs. Using molecular dynamic simulation (MD), the present study investigated the architectural changes of wild-type and mutants EGFR’s kinase domains in order to detect any conformational differences that could be associated with a constitutively activated state and thus to evaluate the differences between the wild-type and its mutated forms. In addition, in order t...
Journal of Cellular Biochemistry, 2019
BackgroundTargeted therapy is a novel, promising approach to anticancer treatment that endeavors to overcome drug resistance to traditional chemotherapies. Patients with the L858R mutation in epidermal growth factor receptor (EGFR) respond to the first generation tyrosine kinase inhibitors (TKIs); however, after one year of treatment, they may become resistant. The T790M mutation is the most probable cause for drug resistance. Third generation drugs, including Osimertinib (AZD9291), are more effective against T790M and other sensitive mutations. Osimertinib is effective against the L844V mutation, has conditional effectiveness for the L718Q mutation, and is ineffective for the Cys797Ser (C797S) mutation. Cells that have both the T790M and C797 mutations are more resistant to third generation drugs. Although research has shown that Osimertinib is an effective treatment for EGFR L844V cells, this has not been shown for cells that have the C797S mutation. This molecular mechanism has n...