+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Insight into binding mechanisms of EGFR allosteric inhibitors using molecular dynamics simulations and free energy calculations



Insight into binding mechanisms of EGFR allosteric inhibitors using molecular dynamics simulations and free energy calculations



Journal of Biomolecular Structure and Dynamics 37(16): 4384-4394



Lung cancer is the leading cause of cancer death, and epidermal growth factor receptor (EGFR) kinase domain mutations are a common cause of non-small-cell lung cancer (NSCLC), a major subtype of lung cancers. Patients harboring most of these mutations respond well to the EGFR inhibitors Gefitinib and Erlotinib initially, but soon develop resistance to them due to the emergence of the gatekeeper mutation T790M. The new-generation inhibitors such as AZD9291, HM61713, CO-1686 and WZ4002 can overcome T790M through covalent binding to Cys 797, but ultimately lose their efficacy upon the emergence of the C797S mutation that abolishes the covalent bonding. Allosteric inhibitors EAI001 and EAI045 are a new type of EGFR inhibitors that bind to EGFR away from the ATP-binding site and not relying on Cys 797. In this study, molecular dynamics simulations and free energy calculations were carried out on EAI001 and EAI045 in complex with EGFR, revealing the detailed inhibitory mechanism of EAI001 and EAI045 as EGFR allosteric inhibitor, which was expected to provide a basis for rational drug design of the EGFR allosteric inhibitors. Communicated by Ramaswamy H. Sarma.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 065819590

Download citation: RISBibTeXText

PMID: 30499387

DOI: 10.1080/07391102.2018.1552197


Related references

Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations. Current Computer-Aided Drug Design 11(2): 124-136, 2015

Insight into the structural mechanism for PKBα allosteric inhibition by molecular dynamics simulations and free energy calculations. Journal of Molecular Graphics and Modelling 48: 36-46, 2014

Exploring resistance mechanisms of HCV NS3/4A protease mutations to MK5172: insight from molecular dynamics simulations and free energy calculations. Molecular Biosystems 11(9): 2568-2578, 2015

Gaining insight into crizotinib resistance mechanisms caused by L2026M and G2032R mutations in ROS1 via molecular dynamics simulations and free-energy calculations. Journal of Molecular Modeling 23(4): 141, 2017

Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations. Plos one 10(12): E0145219, 2015

Molecular insight into the specific binding of ADP-ribose to the nsP3 macro domains of chikungunya and Venezuelan equine encephalitis viruses: molecular dynamics simulations and free energy calculations. Journal of Molecular Graphics and Modelling 29(3): 347-353, 2010

Exploring binding modes of the selected inhibitors to phosphodiesterase delta by all-atom molecular dynamics simulations and free energy calculations. Journal of Biomolecular Structure and Dynamics 37(9): 2415-2429, 2019

Structural insight into the role of Gln293Met mutation on the Peloruside A/Laulimalide association with αβ-tubulin from molecular dynamics simulations, binding free energy calculations and weak interactions analysis. Journal of Computer-Aided Molecular Design 31(7): 643-652, 2017

Insight into the key active sites of af ChiA1 based on molecular dynamics simulations and free energy calculations. Molecular Simulation 42(12): 1024-1028, 2016

Insight into the dynamic interaction between different flavonoids and bovine serum albumin using molecular dynamics simulations and free energy calculations. Journal of Molecular Modeling 19(3): 1039-1047, 2013

Insight into the binding modes of Lassa nucleoprotein complexed with ssRNA by molecular dynamic simulations and free energy calculations. Journal of Biomolecular Structure and Dynamics 33(5): 946-960, 2015

In Silico Design, Extended Molecular Dynamic Simulations and Binding Energy Calculations for a New Series of Dually Acting Inhibitors against EGFR and HER2. 2013

Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations. Molecular Biosystems 9(3): 361-374, 2013

Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site. Nucleic Acids Research 33(2): 725-733, 2005

Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations. Molecular Biosystems 13(4): 736-749, 2017