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Accelerating Scaffold Hopping in Fourth-Generation Epidermal Growth Factor Receptor Inhibitors via Multilevel Virtual
Zhiqi Sun1, Donghui Huo1, Jiangyu Guo1
1State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, Beijing University of Chemical Technology, P.O. Box 53, 15 BeiSanHuan East Road, Beijing 100029, P. R. China.
Abstract:
The epidermal growth factor receptor (EGFR) family plays a crucial role in regulating cell proliferation, apoptosis, and differentiation. However, challenges related to drug resistance have emerged in the clinical applications of this family. This study addresses resistance mediated by the L858R/T790M/C797S EGFR mutation through a multilevel virtual screening strategy that integrates 3D shape similarity screening, multitask deep learning-based activity prediction, molecular docking, and molecular dynamics simulations. From 18 million drug-like molecules screened, 12 candidates underwent in vitro enzymatic testing, leading to the identification of three novel scaffold inhibitors. Compound L15 demonstrated potent inhibitory activity against the L858R/T790M/C797S mutant EGFR (IC50 = 16.43 nM), exhibiting 5-fold selectivity over wild-type EGFR (IC50 = 80.96 nM). Additionally, it exhibited comparable efficacy against the d746-750/T790M/C797S variant (IC50 = 16.53 nM). Interaction analysis revealed that L15 stabilizes its binding conformation via dominant hydrophobic interactions with LEU718 and LEU792, as revealed by free energy decomposition. This work establishes a systematic multilevel virtual screening strategy to overcome EGFR resistance, providing structural and mechanistic insights for the rational design of fourth-generation inhibitors.
Insights
This study developed a novel virtual screening method to find inhibitors for drug-resistant epidermal growth factor receptor (EGFR) mutations. Compound L15 effectively inhibits L858R/T790M/C797S mutant EGFR, offering a new strategy against cancer drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal growth factor receptor (EGFR) signaling is vital for cell functions, but drug resistance, particularly via mutations like L858R/T790M/C797S, limits treatment efficacy.
- Developing novel inhibitors is crucial to overcome acquired resistance in EGFR-targeted therapies.
Purpose of the Study:
- To establish a systematic multilevel virtual screening strategy to identify inhibitors targeting drug-resistant EGFR mutations.
- To discover novel inhibitors effective against the L858R/T790M/C797S and d746-750/T790M/C797S EGFR variants.
Main Methods:
- Integrated 3D shape similarity screening, deep learning-based activity prediction, molecular docking, and molecular dynamics simulations.
- Screened 18 million drug-like molecules, followed by in vitro enzymatic testing of 12 candidates.
- Utilized free energy decomposition to analyze molecular interactions.
Main Results:
- Identified three novel scaffold inhibitors, with Compound L15 showing potent activity against L858R/T790M/C797S mutant EGFR (IC50 = 16.43 nM).
- Compound L15 demonstrated 5-fold selectivity over wild-type EGFR and comparable efficacy against the d746-750/T790M/C797S variant.
- L15 binding is stabilized by hydrophobic interactions with LEU718 and LEU792.
Conclusions:
- The developed multilevel virtual screening strategy is effective for overcoming EGFR resistance.
- Compound L15 represents a promising lead for developing fourth-generation EGFR inhibitors.
- Structural and mechanistic insights are provided for rational drug design against resistant EGFR mutations.
