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Updated: Jul 3, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Identification of potential focal adhesion kinase (FAK) inhibitors: a molecular modeling approach
Sahaya Nadar1,2, Maheshkumar R Borkar1, Tabassum Khan1
1Department of Pharmaceutical Chemistry, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India.
Abstract:
Focal adhesion kinase (FAK) is an enzyme of paramount importance as it is involved in several critical roles, which are linked to proliferation of cancer cells. FAK is quintessential for cancer cell mitigation, adhesion and survival, downregulation of which interferes with the growth of cancer cells. The expression of FAK is elevated in breast cancer, hepatocellular carcinomas, neuroblastoma cells, demonstrating the need for FAK inhibitors as a potential treatment. Based on an in silico drug screen, the study aimed to identify potential FAK inhibitors. 3180 molecules retrieved from the Zinc database comprising biogenic molecules, FDA-approved drugs and compounds in clinical trials were screened against the FAK enzyme (PDB:2ETM). The XP docking study of the best 51 ligands revealed that ZINC02033589 (Silymarin) showed good binding to FAK with -10.97 kcal/mol dock score followed by ZINC00518397 with -8.23 kcal/mol and ZINC03831112 - 8.07 kcal/mol. The interactions of the top three ligands with FAK were further validated by molecular dynamic simulation study of 100 ns and MM-GBSA calculations. The ΔG of binding of ZINC02033589, ZINC00518397 and ZINC03831112 was found to be -59.09, -45.08 and -48.53 kcal/mol respectively. The study established the fact that among the three molecules, ZINC02033589 showed good stability and binding towards FAK. These results could usher in the development of potential FAK inhibitor entities, that could be persuaded and substantiated by the molecules identified in this study for subsequent synthetic and bioactivity research studies.
Insights
This study identified potential focal adhesion kinase (FAK) inhibitors using computational screening. Silymarin (ZINC02033589) demonstrated strong binding and stability, suggesting its potential for cancer treatment development.
Area of Science:
- Biochemistry
- Computational Chemistry
- Pharmacology
Background:
- Focal adhesion kinase (FAK) plays a critical role in cancer cell proliferation, adhesion, and survival.
- Elevated FAK expression is observed in various cancers, including breast cancer and hepatocellular carcinoma.
- Targeting FAK with inhibitors presents a promising therapeutic strategy for cancer treatment.
Purpose of the Study:
- To identify potential focal adhesion kinase (FAK) inhibitors through in silico drug screening.
- To evaluate the binding affinity and stability of identified compounds with FAK.
- To provide a basis for the development of novel FAK-targeting cancer therapies.
Main Methods:
- In silico screening of 3180 molecules from the Zinc database against the FAK enzyme (PDB:2ETM).
- XP docking studies were performed to assess ligand-protein interactions.
- Molecular dynamic simulations and MM-GBSA calculations were used to validate the binding of top-ranked compounds.
Main Results:
- Silymarin (ZINC02033589) exhibited the highest binding affinity to FAK (-10.97 kcal/mol), followed by ZINC00518397 (-8.23 kcal/mol) and ZINC03831112 (-8.07 kcal/mol).
- Molecular dynamics and MM-GBSA calculations confirmed strong binding, with Silymarin showing the most favorable binding free energy (ΔG = -59.09 kcal/mol).
- ZINC02033589 demonstrated good stability and binding interactions with FAK.
Conclusions:
- Silymarin (ZINC02033589) is a promising candidate for a FAK inhibitor.
- The identified compounds warrant further investigation for synthetic modification and bioactivity studies.
- This study supports the development of novel FAK inhibitor entities for cancer therapy.
