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

Wan, Shanhe; Yan, Ruohong; Jiang, Ying; Li, Zhonghuang; Zhang, Jiajie; Wu, Xia

doi:10.1080/07391102.2018.1552197

Cited by 21 publications

(13 citation statements)

References 36 publications

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“…In addition, allosteric inhibitors may not need to exhibit nanomolar affinity to compete with the intracellular high-concentration ATP, making it easier to identify weak binding inhibitors, ranging from fragments to hit and lead compounds, and treatment of indications beyond cancer may be feasible. [15] With these attractive features, allosteric EGFR inhibitors are now being extensively studied as a new generation of TKIs combating NSCLC drug resistance. [16] In the present study, we attempt to systematically investigate the drug response profile of all reported allosteric EGFR inhibitors to NSCLC clinically significant missense mutations harboring in EGFR kinase domain, aiming at elucidating the molecular mechanism of allosteric inhibitor interaction with these mutations and predicting potential drug resistance or sensitization of allosteric inhibitors upon certain mutations.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Zhao

Zhu

Gao

2021

J Chinese Chemical Soc

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Human epidermal growth factor receptor (EGFR) is an attractive anti-non-small cell lung cancer (anti-NSCLC) druggable target, but many traditional adenosine triphosphate (ATP)-competitive EGFR inhibitors have been clinically observed to eventually establish acquired resistance due to kinase mutations. Allosteric inhibitors represent a new direction of EGFR-targeted therapy, which have been successfully developed since 2016 to overcome the widely occurring kinase drug-resistant mutations T790M/C797S [Jia Y, et al. Nature 2016; 534: 129-132].In this study, a systematic inhibitor response-to-mutation profile of 11 reported EGFR allosteric inhibitors against 17 clinically significant EGFR missense muta-

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Section: Introductionmentioning

confidence: 99%

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Zhao

Zhu

Gao

2021

J Chinese Chemical Soc

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“…The selected five complexes protein–ligand were subjected to 100 ns (nanoseconds) simulations of molecular dynamics (MD) under constant pressure and temperature conditions and the stability of the molecules can be understood with simulations of MD complexes ( Sakthivel and Habeeb, 2018 , Tanneeru et al, 2015 , Tanneeru and Guruprasad, 2013 , Wan et al, 2019 ). All the simulations of MD were conducted by using Gromacs 2018, Ubuntu-18.04 LTS Linux platform.…”

Section: Methodsmentioning

confidence: 99%

In-silico study of seaweed secondary metabolites as AXL kinase inhibitors

Nagamalla

Kumar

Chintakindi

et al. 2022

Saudi Journal of Biological Sciences

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“…High concentration ATP screening further confirms that EAI001 was potentially non‐ATP‐competitive (allosteric) inhibitor. Further optimization of its phenyl group yielded a more potent inhibitor EAI045 ( 25 ) against EGFR L858R/T790M IC 50 =3 nM) and maintained 1000‐fold selectivity against wild‐type EGFR [100] . Selectivity of EAI045 ( 25 ) was evaluated in 250 protein kinase assay at 1 μM of EAI045 and no other kinases were inhibited by more than 20 % [101] .…”

Section: Kinase Inhibitors For Tackling Nsclcmentioning

confidence: 99%

Next‐Generation Kinase Inhibitors Targeting Specific Biomarkers in Non‐Small Cell Lung Cancer (NSCLC): A Recent Overview

2021

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Lung cancer causes many deaths globally. Mutations in regulatory genes, irregularities in specific signal transduction events, or alterations of signalling pathways are observed in cases of non‐small cell lung cancer (NSCLC). Over the past two decades, a few kinases have been identified, validated, and studied as biomarkers for NSCLC. Among them, EGFR, ALK, ROS1, MET, RET, NTRK, and BRAF are regarded as targetable biomarkers to cure and/or control the disease. In recent years, the US Food and Drug Administration (FDA) approved more than 15 kinase inhibitors targeting these NSCLC biomarkers. The kinase inhibitors significantly improved the progression‐free survival (PFS) of NSCLC patients. Challenges still remain for metastatic diseases and advanced NSCLC cases. New discoveries of potent kinase inhibitors and rapid development of modern medical technologies will help to control NSCLC cases. This article provides an overview of the discoveries of various types of kinase inhibitors against NSCLC, along with medicinal chemistry aspects and related developments in next‐generation kinase inhibitors that have been reported in recent years.

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

Cited by 21 publications

References 36 publications

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

Molecular analysis and systematic profiling of allosteric inhibitor response to clinically significant epidermal growth factor receptor missense mutations in non‐small cell lung cancer

In-silico study of seaweed secondary metabolites as AXL kinase inhibitors

Next‐Generation Kinase Inhibitors Targeting Specific Biomarkers in Non‐Small Cell Lung Cancer (NSCLC): A Recent Overview

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