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Identification of inhibitors targeting HIF-2α/c-Myc by molecular docking and MM-GBSA technology
Lijun Feng1, Chuance Sun1, Xiaohua Sun1
1College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China.
Abstract:
The treatment of ccRCC by targeting hypoxia-inducible factor HIF-2α is currently a direct and effective method. Studies have shown that HIF-2α and c-Myc cooperate to promote ccRCC tumor progression, and the overexpression of c-Myc is related to the progress and drug resistance of most human cancers. Although HIF-2α and c-Myc are important drug targets, their dual inhibitors are still lacking. We used virtual screening tools (mainly including molecular docking and MM-GBSA technology) to obtain some well-listed compounds that can potentially target HIF-2α and c-Myc and used molecular dynamics simulations to study their binding with these protein systems. Using a structure-based screening scheme, a batch of top-ranking compounds were selected, and their binding affinities were predicted of these compounds were performed. Representative compound C93106, C43257, and C41580 all showed good comprehensive binding score. Our results indicate that the target compounds can all form key interactions with the active site of the protein, and 30 ns molecular dynamic simulation of the complex system indicates a stable binding conformation. This research laid the foundation for the development of more effective and specific HIF-2α and c-Myc dual-target inhibitors.
Insights
Researchers identified novel compounds targeting both hypoxia-inducible factor HIF-2α and c-Myc, crucial in kidney cancer progression. This discovery paves the way for developing dual-target inhibitors against clear cell renal cell carcinoma (ccRCC).
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- Targeting hypoxia-inducible factor HIF-2α is an effective treatment for clear cell renal cell carcinoma (ccRCC).
- HIF-2α and c-Myc cooperate in ccRCC progression, with c-Myc overexpression linked to cancer advancement and drug resistance.
- Currently, dual inhibitors targeting both HIF-2α and c-Myc are unavailable.
Purpose of the Study:
- To identify novel compounds with dual inhibitory potential against HIF-2α and c-Myc.
- To computationally screen and validate compounds for targeting these key proteins in ccRCC.
Main Methods:
- Employed virtual screening, including molecular docking and MM-GBSA, to identify potential dual inhibitors.
- Utilized molecular dynamics simulations to assess the binding stability and interactions of selected compounds.
- Structure-based screening was performed to rank and select promising candidate compounds.
Main Results:
- Identified several compounds with potential to target both HIF-2α and c-Myc.
- Compounds C93106, C43257, and C41580 demonstrated strong binding affinities and favorable scores.
- Molecular dynamics simulations confirmed stable binding conformations of these compounds within the protein active sites.
Conclusions:
- The identified compounds form key interactions within the protein active sites, suggesting potent inhibitory capabilities.
- This study provides a foundation for developing novel, specific dual-target inhibitors for HIF-2α and c-Myc.
- These findings could lead to more effective therapeutic strategies for ccRCC and other cancers.
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