ArticleScientific reports2020
KRAS(G12C)-AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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Who cites it
24 citing papers in PubMed, 43 citations in OpenAlex.
- Structural and Energetic Determinants of Monobody Recognition of Oncogenic KRAS Variants.bioRxiv : the preprint server for biology · 2026Article
- Design, synthesis, and anticancer evaluation of novel pyrrole-pyrazoline/chalcone hybrids:RSC medicinal chemistry · 2026Article
- Bioinformatics and computational exploration of novel inhibitors targeting KRAS G12C mutant protein in lung adenocarcinoma.Discover oncology · 2026Article
- Theoretical study of KRAS G12C secondary mutations influencing inhibitor resistance.Biophysics and physicobiology · 2026Article
- Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells.Cell death & disease · 2025Article
- Investigation of potential KRASG12D inhibitors: a comparative study between MRTX1133 and natural compounds via computational structural biology approaches.BMC research notes · 2025Article
- Binding modes of the KRAS(G12C) inhibitors GDC-6036 and LY3537982 revealed by all atom molecular dynamics simulations.Scientific reports · 2025Article
- Development of Receptor Desolvation Scoring and Covalent Sampling in DOCK 6: Methods Evaluated on a RAS Test Set.Journal of chemical information and modeling · 2025Article
- Therapeutic strategies for KRAS G12C-mutant non-small cell lung cancer: from bench to bedside and beyond.Frontiers in pharmacology · 2025Review
- CHARMM-GUI PDB Reader and Manipulator: Covalent Ligand Modeling and Simulation.Journal of molecular biology · 2024Article
- RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.The Journal of cell biology · 2024Article
- Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.Science advances · 2023Article
- In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders.Journal of chemical information and modeling · 2023Article
- The current state of the art and future trends in RAS-targeted cancer therapies.Nature reviews. Clinical oncology · 2022Review
- Computer-Aided Drug Design Boosts RAS Inhibitor Discovery.Molecules (Basel, Switzerland) · 2022Review
- Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers.Cancers · 2022Review
- The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target-a narrative review.Translational lung cancer research · 2022Review
- A saturation mutagenesis screen uncovers resistant and sensitizing secondaryProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Identification of New KRAS G12D Inhibitors through Computer-Aided Drug Discovery Methods.International journal of molecular sciences · 2022Article
- Mechanistic insights into the clinical Y96D mutation with acquired resistance to AMG510 in the KRASFrontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
1 author at 1 institution in 1 country.
Funding
Abstract
The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. On the molecular level, however, the interaction dynamics of this covalently bound drug-protein complex has been undetermined. Here, we disclose the interaction dynamics of the KRAS(G12C)-AMG 510 complex by long timescale all-atom molecular dynamics (MD) simulations (total of 75 μs). Moreover, we investigated the influence of the recently reported post-translational modification (PTM) of KRAS' N-terminus, removal of initiator methionine (iMet1) with acetylation of Thr2, to this complex. Our results demonstrate that AMG 510 does not entrap KRAS into a single conformation, as one would expect based on the crystal structure, but rather into an ensemble of conformations. AMG 510 binding is extremely stable regardless of highly dynamic interface of KRAS' switches. Overall, KRAS(G12C)-AMG 510 complex partially mimic the native dynamics of GDP bound KRAS; however, AMG 510 stabilizes the α3-helix region. N-terminally modified KRAS displays similar interaction dynamics with AMG 510 as when Met1 is present, but this PTM appears to stabilize β2-β3-loop. These results provide novel conformational insights on the molecular level to KRAS(G12C)-AMG 510 interactions and dynamics, providing new perspectives to RAS related drug discovery.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.