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Updated: Apr 15, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
In silico identification of novel kinase inhibitors by targeting B-Raf(v660e) from natural products database
Zi-jie Wang1, Zhi-ning Wan, Xu-dong Chen
1School of Life Sciences and Key Laboratory of Bio-resources, Ministry of Education, & State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610064, China.
Abstract:
The Ras/Raf/MEK/ERK (MAPK) signaling pathway has gained much attention from scientific community for therapeutic intervention in the past decades, specifically in oncology. Notably, a most prevalent B-Raf(v600e) mutant in Raf kinase family exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, virtual screening is applied to identify its potential inhibitors. Following the 25 ns molecular dynamic (MD) simulations, ZINC38541768, ZINC38541767, and ZINC12496469 are identified as B-Raf(v600e) potential inhibitors in a DFG-in conformation. Furthermore, according to the molecular mechanics/generalized born surface area (MM/GBSA) method, these three small molecules exhibit similar and good binding affinity toward B-Raf(v600e) (-38.76 kcal mol(-1), -42.60 kcal mol(-1), and -39.04 kcal mol(-1)). At the same time, several critical residues, such as I463, V471 in the P-loop, and DFG motif residue D594 within the A-loop, are also well clarified. All these results may not only indicate some future applications of inhibitors targeting B-Raf(v600e), but also benefit B-Raf(v600e) harboring cancer patients.
Insights
Researchers identified potential B-Raf(v600e) inhibitors using virtual screening and molecular dynamics. Three compounds (ZINC38541768, ZINC38541767, ZINC12496469) showed good binding affinity, offering new therapeutic strategies for B-Raf(v600e) driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- The Ras/Raf/MEK/ERK (MAPK) signaling pathway is a key target in cancer therapy.
- The B-Raf(v600e) mutation leads to constitutive MAPK pathway activation, driving cancer progression.
- Targeting B-Raf(v600e) offers a promising therapeutic strategy for various cancers.
Purpose of the Study:
- To identify potential small molecule inhibitors of the B-Raf(v600e) mutant kinase.
- To evaluate the binding affinity and interactions of identified inhibitors with B-Raf(v600e).
Main Methods:
- Virtual screening was employed to identify potential B-Raf(v600e) inhibitors.
- Molecular dynamics (MD) simulations were performed for 25 ns to analyze inhibitor-protein interactions.
- Molecular mechanics/generalized Born surface area (MM/GBSA) was used to calculate binding affinities.
Main Results:
- Three compounds (ZINC38541768, ZINC38541767, ZINC12496469) were identified as potential B-Raf(v600e) inhibitors in a DFG-in conformation.
- These compounds exhibited significant binding affinities towards B-Raf(v600e), with MM/GBSA values of -38.76, -42.60, and -39.04 kcal/mol, respectively.
- Key interactions with residues such as I463, V471, and D594 were elucidated.
Conclusions:
- The identified small molecules demonstrate potential as therapeutic agents targeting B-Raf(v600e).
- These findings provide a basis for future drug development against B-Raf(v600e) driven cancers.
- This study contributes to the understanding of B-Raf(v600e) inhibition mechanisms.
