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Updated: Sep 19, 2025
Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
In Silico Identification of Novel and Potent Inhibitors Against Mutant BRAF (V600E), MD Simulations, Free Energy
Vikas Yadav1, Mohammad Kashif1, Zenab Kamali2
1School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
Abstract:
BRAF is a proto oncogene that functions as a key signal transducer in the MAPK-ERK pathway, which regulates cell growth, division, and survival. Mutations in BRAF, particularly the V600E substitution in its kinase domain, are major drivers in melanoma and several other metastatic cancers, including breast, colorectal, NSCLC, and gastrointestinal cancers. In this study, novel inhibitors targeting the BRAF(V600E) mutant using a structure-based drug design approach are identified. Four chemical libraries ChemDiv Kinase, ChemDiv Anticancer, NCI, and ChEMBL Kinase SARfari are screened. Compounds from the ChemDiv Anticancer database show better Glide scores comparable to the FDA-approved BRAF inhibitor Vemurafenib. The compounds P184-1419 and P184-1479 score -12.688 and -12.012 kcal/mol, respectively, versus -14.288 kcal/mol for Vemurafenib. Top hits are further validated using GOLD docking, X-score ranking, and interaction profiling via LigPlot. Molecular dynamics simulations, principal component analysis, and free energy calculations confirm the stability of protein-ligand complexes. Biolayer interferometry assays reveal P184-1419 exhibits stronger binding affinity (KD = 151 μM) than Vemurafenib (KD = 437 μM). These findings suggest P184-1419 is a promising lead compound against BRAF(V600E), offering potential for future development of more effective cancer therapies.
Insights
Researchers identified novel BRAF(V600E) inhibitors using structure-based design. Compound P184-1419 demonstrated superior binding affinity, showing potential as a new cancer therapy lead.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- BRAF proto-oncogene is crucial in the MAPK-ERK pathway regulating cell growth.
- BRAF V600E mutations drive melanoma and other metastatic cancers.
- Targeting BRAF V600E is a key strategy in cancer therapy.
Purpose of the Study:
- To identify novel inhibitors targeting the BRAF(V600E) mutant.
- To utilize structure-based drug design for discovering potent BRAF inhibitors.
- To evaluate potential lead compounds for cancer treatment.
Main Methods:
- Screening of four chemical libraries (ChemDiv Kinase, ChemDiv Anticancer, NCI, ChEMBL Kinase SARfari).
- Structure-based drug design, Glide docking, GOLD docking, and X-score ranking.
- Molecular dynamics simulations, principal component analysis, free energy calculations, and biolayer interferometry assays.
Main Results:
- Compounds from the ChemDiv Anticancer database showed promising Glide scores.
- P184-1419 and P184-1479 exhibited strong binding potential compared to Vemurafenib.
- P184-1419 displayed a significantly higher binding affinity (KD = 151 μM) than Vemurafenib (KD = 437 μM).
Conclusions:
- P184-1419 is a promising lead compound for targeting BRAF(V600E).
- The identified inhibitors hold potential for developing novel and effective cancer therapies.
- Structure-based drug design is effective for discovering targeted cancer therapeutics.
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