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Synthesis, docking, 4D-QSAR and dynamics simulation of sorbamide derivatives as EGFR inhibitors
1Jiangxi Province Key Laboratory of Drug Target Discovery and Validation, School of Pharmaceutical Science, Jiangxi Medical College, Nanchang University, Nanchang, China.
Abstract:
The epidermal growth factor receptor (EGFR), a validated therapeutic target in oncology, demonstrates overexpression across multiple neoplastic cell types and plays a critical role in tumorigenesis. This investigation reports the strategic synthesis and evaluation of antiproliferative efficacy for novel sorbamide derivatives designed as EGFR inhibitors. Several synthesized compounds exhibited moderate inhibitory effects against EGFR-overexpressed A431 carcinoma cells, and among them, compound 7d demonstrated superior potency relative to the reference agent Gefitinib with an IC50 value of 19.1 µM. A predictive 4D-QSAR model was successfully developed, exhibiting satisfactory statistical parameters ( = 0.81, = 0.62, = 0.60, = 0.71). Complementary computational analyses through covalent docking and molecular dynamics simulations elucidated the molecular interaction mechanism, revealing covalent bond formation between the sorbamide scaffold and the conserved Cys797 residue in the EGFR catalytic domain.
Insights
Novel sorbamide derivatives were synthesized as epidermal growth factor receptor (EGFR) inhibitors. Compound 7d showed superior antiproliferative efficacy against EGFR-overexpressed cancer cells compared to Gefitinib.
Area of Science:
- Medicinal Chemistry
- Oncology
- Computational Chemistry
Background:
- Epidermal growth factor receptor (EGFR) is a key target in oncology due to its overexpression in various cancers.
- EGFR signaling pathways are critical for tumor cell proliferation and survival.
Purpose of the Study:
- To design, synthesize, and evaluate novel sorbamide derivatives as potential EGFR inhibitors.
- To investigate the antiproliferative activity of these compounds against EGFR-overexpressing cancer cells.
- To develop a predictive 4D-QSAR model and elucidate the molecular interactions with EGFR.
Main Methods:
- Synthesis of novel sorbamide derivatives.
- In vitro antiproliferative assays using A431 carcinoma cells.
- Development of a 4D-Quantitative Structure-Activity Relationship (4D-QSAR) model.
- Covalent docking and molecular dynamics simulations.
Main Results:
- Several synthesized sorbamide derivatives demonstrated moderate EGFR inhibitory effects.
- Compound 7d exhibited superior potency (IC50 = 19.1 µM) compared to Gefitinib.
- A robust 4D-QSAR model was established with good statistical validation (=0.81, =0.62).
- Computational analyses revealed covalent binding of sorbamides to the Cys797 residue in EGFR.
Conclusions:
- Novel sorbamide derivatives show promise as EGFR inhibitors for cancer therapy.
- Compound 7d represents a potent lead compound for further drug development.
- The developed 4D-QSAR model can guide the design of future EGFR inhibitors.
- Understanding the covalent interaction mechanism provides insights for targeted drug design.
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