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Virtual Screening, Molecular Dynamics Simulation, and Bioactivity Assessment Validate T13074 as a Dual-target
Dang Fan1, Haifeng Dong1, Anqi Li1
1School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, China.
Objectives:
The objective of this study is to identify dual-target inhibitors against EGFR/c-Met through virtual screening, dynamic simulation, and biological activity evaluation. This endeavor is aimed at overcoming the challenge of drug resistance induced by L858R/T790M mutants.
Methods:
Active structures were gathered to construct sets of drug molecules. Next, property filtering was applied to the drug structures within the compound library. Active compounds were then identified through virtual screening and cluster analysis. Subsequently, we conducted MTT antitumor activity evaluation and kinase inhibition assays for the active compounds to identify the most promising candidates. Furthermore, AO staining and JC-1 assays were performed on the selected compounds. Ultimately, the preferred compounds underwent molecular docking and molecular dynamics simulation with the EGFR and c-Met proteins, respectively.
Results:
The IC50 of T13074 was determined as 2.446 μM for EGFRL858R/T790M kinase and 7.401 nM for c-Met kinase, underscoring its potential in overcoming EGFRL858R/T790M resistance. Additionally, T13074 exhibited an IC50 of 1.93 μM on the H1975 cell. Results from AO staining and JC-1 assays indicated that T13074 induced tumor cell apoptosis in a concentration-dependent manner. Notably, the binding energy between T13074 and EGFR protein was found to be -90.329 ± 16.680 kJ/mol, while the binding energy with c-Met protein was -139.935 ± 17.414 kJ/mol.
Conclusion:
T13074 exhibited outstanding antitumor activity both in vivo and in vitro, indicating its potential utility as a dual-target EGFR/c-Met inhibitor. This suggests its promising role in overcoming EGFR resistance induced by the L858R/T790M mutation.
Insights
This study identifies T13074 as a potent dual-target inhibitor against EGFR/c-Met, demonstrating significant antitumor activity. It offers a promising strategy to overcome drug resistance caused by L858R/T790M mutations in EGFR.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Drug resistance to Epidermal Growth Factor Receptor (EGFR) inhibitors, particularly due to L858R/T790M mutations, poses a significant clinical challenge.
- Developing dual-target inhibitors against EGFR and c-Met is a promising strategy to overcome acquired resistance and improve therapeutic efficacy.
Purpose of the Study:
- To identify novel dual-target inhibitors effective against EGFR/c-Met, focusing on overcoming L858R/T790M-induced drug resistance.
- To evaluate the in vitro antitumor activity and molecular mechanisms of promising candidate compounds.
Main Methods:
- Virtual screening and cluster analysis were employed to identify potential dual-target inhibitors from a compound library.
- In vitro assays including MTT, kinase inhibition, AO staining, and JC-1 were performed to assess antitumor activity and apoptosis induction.
- Molecular docking and molecular dynamics simulations were conducted to elucidate the binding interactions of the lead compound with EGFR and c-Met proteins.
Main Results:
- The compound T13074 demonstrated potent inhibitory activity against both EGFRL858R/T790M kinase (IC50 = 2.446 μM) and c-Met kinase (IC50 = 7.401 nM).
- T13074 exhibited significant antitumor effects on H1975 cells (IC50 = 1.93 μM) and induced apoptosis in a concentration-dependent manner.
- Molecular simulations revealed favorable binding energies for T13074 with both EGFR (-90.329 ± 16.680 kJ/mol) and c-Met (-139.935 ± 17.414 kJ/mol).
Conclusions:
- T13074 displays potent in vitro antitumor activity and acts as a dual-target inhibitor of EGFR/c-Met.
- The compound shows significant potential for overcoming EGFR resistance mediated by L858R/T790M mutations.
- T13074 represents a promising therapeutic candidate for treating resistant cancers driven by EGFR and c-Met signaling.
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