ArticleBiochemistry2009
Quantitative prediction of fold resistance for inhibitors of EGFR.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
29 citing papers in PubMed, 77 citations in OpenAlex.
- Machine learning based personalized drug response prediction for lung cancer patients.Scientific reports · 2022Article
- A small-molecule compound D6 overcomes EGFR-T790M-mediated resistance in non-small cell lung cancer.Communications biology · 2021Article
- Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Dissecting the molecular recognition of dual lapatinib derivatives for EGFR/HER2.Journal of computer-aided molecular design · 2020Article
- Discovery of aminopyridine-containing spiro derivatives as EGFR mutations inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- Insights into an alternative benzofuran binding mode and novel scaffolds of polyketide synthase 13 inhibitors.Journal of molecular modeling · 2019Article
- Identification of a Water-Coordinating HER2 Inhibitor by Virtual Screening Using Similarity-Based Scoring.Biochemistry · 2018Article
- Structure and energy based quantitative missense variant effect analysis provides insights into drug resistance mechanisms of anaplastic lymphoma kinase mutations.Scientific reports · 2018Article
- Epidermal growth factor receptor somatic mutation analysis in 354 Chinese patients with non-small cell lung cancer.Oncology letters · 2018Article
- The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review).International journal of molecular medicine · 2017Review
- Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).The Journal of biological chemistry · 2015Article
- Pharmacophore-based similarity scoring for DOCK.The journal of physical chemistry. B · 2015Article
- Luteolin is effective in the non-small cell lung cancer model with L858R/T790M EGF receptor mutation and erlotinib resistance.British journal of pharmacology · 2014Article
- Quantum coupled mutation finder: predicting functionally or structurally important sites in proteins using quantum Jensen-Shannon divergence and CUDA programming.BMC bioinformatics · 2014Article
- Strategies for lead discovery: application of footprint similarity targeting HIVgp41.Bioorganic & medicinal chemistry · 2014Article
- Sequence selectivity of the cleavage sites induced by topoisomerase I inhibitors: a molecular dynamics study.Nucleic acids research · 2013Article
- Ligand binding and dynamics of the monomeric epidermal growth factor receptor ectodomain.Proteins · 2013Article
- Accurate calculation of mutational effects on the thermodynamics of inhibitor binding to p38α MAP kinase: a combined computational and experimental study.Journal of chemical theory and computation · 2013Article
- Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations.Journal of molecular modeling · 2013Article
- Differences in the binding affinities of ErbB family: heterogeneity in the prediction of resistance mutants.PloS one · 2013Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
Clinical use of ATP-competitive inhibitors of the epidermal growth factor receptor (EGFR) kinase domain can lead to an acquired drug resistant mutant L858R&T790M which dramatically reduces binding affinity relative to a prevalent cancer causing mutation L858R. In this study, we have used molecular dynamics (MD) computer simulations, free energy calculations (MM-GBSA method), and per-residue footprint analysis to characterize binding of three inhibitors (erlotinib, gefitinib, and AEE788) with wildtype EGFR and three mutants. The goal is to characterize how variation in structure and energy correlate with changes in experimental activities and to deduce origins of drug resistance. For seven fold resistance values, each computed from the difference of two independent computer simulations, excellent agreement was obtained with available experimental data (r2 = 0.84). Importantly, the results correctly predict that affinity will increase as a result of L858R and decrease due to L858R&T790M. Per-residue analysis shows an increase in favorable packing at the site of the methionine mutation reaffirming that a steric clash hypothesis is unlikely; however, large losses in van der Waals, Coulombic, and H-bond interactions strongly suggest that resistance is not due solely to changes in affinity for the native substrate ATP as recently proposed. Instead, the present results indicate that drug resistance more likely involves disruption of favorable interactions, including a water-mediated H-bond network between the ligands and residues T854, T790, and Q791, which could have important implication for guiding rational design of inhibitors with improved resistance profiles.
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Registered trials
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