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Discovery of dual kinase inhibitors targeting VEGFR2 and FAK: structure-based pharmacophore modeling, virtual
Marwa A Fouad1,2, Alaa A Osman3, Noha M Abdelhamid3
1Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt. marwa.fouad@pharma.cu.edu.eg.
Abstract:
VEGFR2 and FAK signaling pathways are interconnected and have synergistic effects on tumor angiogenesis, growth, and metastasis. Thus, instead of the conventional targeting of each of these proteins individually with a specific inhibitor, the present work aimed to discover novel dual inhibitors targeting both VEGFR2 and FAK exploiting their association. To this end, receptor-based pharmacophore modeling technique was opted to generate 3D pharmacophore models for VEGFR2 and FAK type II kinase inhibitors. The generated pharmacophore models were validated by assessing their ability to discriminate between active and decoy compounds in a pre-compiled test set of VEGFR2 and FAK active compounds and decoys. ZINCPharmer web tool was then used to screen the ZINC database purchasable subset using the validated pharmacophore models retrieving 42,616 hits for VEGFR2 and 28,475 hits for FAK. Subsequently, they were filtered using various filters leaving 13,023 and 6,832 survived compounds for VEGFR2 and FAK, respectively, with 124 common compounds. Based on molecular docking simulations, thirteen compounds were found to satisfy all necessary interactions with VEGFR2 and FAK kinase domains. Thus, they are predicted to have a possible dual VEGFR2/FAK inhibitory activity. Finally, SwissADME web tool showed that compound ZINC09875266 is not only promising in terms of binding pattern to our target kinases, but also in terms of pharmacokinetic properties.
Insights
Researchers identified novel dual inhibitors targeting both VEGFR2 and FAK, crucial for blocking tumor growth and metastasis. This approach offers a promising strategy beyond single-target inhibition for cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- VEGFR2 and FAK signaling pathways are key drivers of tumor angiogenesis, growth, and metastasis.
- Conventional therapies targeting VEGFR2 or FAK individually have limitations.
- Targeting both pathways simultaneously offers a synergistic approach to cancer treatment.
Purpose of the Study:
- To discover novel dual inhibitors targeting both VEGFR2 and FAK by exploiting their interconnected signaling pathways.
- To develop a computational strategy for identifying compounds with dual inhibitory activity against VEGFR2 and FAK.
Main Methods:
- Receptor-based pharmacophore modeling was employed to generate 3D pharmacophore models for VEGFR2 and FAK type II kinase inhibitors.
- Pharmacophore models were validated using active compounds and decoys.
- The ZINC database was screened using validated models, followed by filtering and molecular docking simulations.
- SwissADME web tool was used for pharmacokinetic property assessment.
Main Results:
- Validated pharmacophore models successfully discriminated between active and decoy compounds.
- Virtual screening identified 124 common compounds potentially targeting both VEGFR2 and FAK.
- Molecular docking revealed thirteen compounds with favorable interactions within the kinase domains of VEGFR2 and FAK.
- Compound ZINC09875266 demonstrated promising binding patterns and favorable pharmacokinetic properties.
Conclusions:
- The study successfully identified potential dual inhibitors of VEGFR2 and FAK using a computational approach.
- Compound ZINC09875266 is a promising candidate for further development as a dual VEGFR2/FAK inhibitor.
- This strategy offers a novel therapeutic avenue for cancers driven by VEGFR2 and FAK signaling.
