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Identification of Novel Potential VEGFR-2 Inhibitors Using a Combination of Computational Methods for Drug Discovery
Mohammad M Al-Sanea1, Garri Chilingaryan2,3, Narek Abelyan3,4
1Pharmaceutical Chemistry Department, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia.
Abstract:
The vascular endothelial growth factor receptor 2 (VEGFR-2) is largely recognized as a potent therapeutic molecular target for the development of angiogenesis-related tumor treatment. Tumor growth, metastasis and multidrug resistance highly depends on the angiogenesis and drug discovery of the potential small molecules targeting VEGFR-2, with the potential anti-angiogenic activity being of high interest to anti-cancer research. Multiple small molecule inhibitors of the VEGFR-2 are approved for the treatment of different type of cancers, with one of the most recent, tivozanib, being approved by the FDA for the treatment of relapsed or refractory advanced renal cell carcinoma (RCC). However, the endogenous and acquired resistance of the protein, toxicity of compounds and wide range of side effects still remain critical issues, which lead to the short-term clinical effects and failure of antiangiogenic drugs. We applied a combination of computational methods and approaches for drug design and discovery with the goal of finding novel, potential and small molecule inhibitors of VEGFR2, as alternatives to the known inhibitors' chemical scaffolds and components. From studying several of these compounds, the derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione in particular were identified.
Insights
Researchers explored novel small molecule inhibitors targeting vascular endothelial growth factor receptor 2 (VEGFR-2) to overcome cancer treatment resistance and side effects. Pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione derivatives show promise as alternatives to existing anti-angiogenic drugs.
Area of Science:
- Oncology
- Pharmacology
- Medicinal Chemistry
Background:
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key target for anti-angiogenesis cancer therapies.
- Approved VEGFR-2 inhibitors like tivozanib show efficacy but face challenges including resistance, toxicity, and side effects.
- Limitations of current anti-angiogenic drugs necessitate the discovery of novel small molecule inhibitors.
Purpose of the Study:
- To identify novel small molecule inhibitors of VEGFR-2 using computational drug design.
- To discover alternative chemical scaffolds to overcome limitations of existing VEGFR-2 inhibitors.
- To find potential drug candidates with improved anti-angiogenic activity for cancer treatment.
Main Methods:
- Application of computational methods for drug design and discovery.
- Screening of potential small molecule inhibitors targeting VEGFR-2.
- Identification of promising chemical scaffolds through structure-activity relationship analysis.
Main Results:
- Novel small molecule inhibitors of VEGFR-2 were identified through computational approaches.
- Derivatives of pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione emerged as particularly promising scaffolds.
- These compounds represent potential alternatives to current anti-angiogenic therapies.
Conclusions:
- Computational drug design can effectively identify novel VEGFR-2 inhibitors.
- Pyrido[1,2-a]pyrimidin-4-one and isoindoline-1,3-dione derivatives offer a promising avenue for developing new anti-cancer agents.
- Further research into these novel scaffolds may lead to improved treatments for angiogenesis-dependent cancers.
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