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Updated: Aug 9, 2025
A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Discovery of VEGFR inhibitors through virtual screening and energy assessment
Jurnal Reang1, Kalicharan Sharma1, Prabodh C Sharma1
1Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, New Delhi, India.
Abstract:
Vascular endothelial growth factor receptor-2 (VEGFR-2) is crucial in promoting tumor angiogenesis and cancer metastasis. Thus, inhibition of VEGFR-2 has appeared as a good tactic for cancer treatment. To find out novel VEGFR-2 inhibitors, first, the PDB structure of VEGFR-2, 6GQO, was selected based on atomic nonlocal environment assessment (ANOLEA) and PROCHECK assessment. 6GQO was then further used for structure-based virtual screening (SBVS) of different molecular databases, including US-FDA approved drugs, US-FDA withdrawn drugs, may bridge, MDPI, and Specs databases using Glide. Based on SBVS, receptor fit, drug-like filters, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis of 427877 compounds, the best 22 hits were selected. From the 22 hits, hit 5 complex with 6GQO was put through molecular mechanics/generalized born surface area (MM/GBSA) study and hERG binding. The MM/GBSA study revealed that hit 5 possesses lesser binding free energy with more inferior stability in the receptor pocket than the reference compound. The VEGFR-2 inhibition assay of hit 5 disclosed an IC50 of 165.23 nM against VEGFR-2, which can be possibly enhanced through structural modifications.
Insights
Researchers identified a novel compound that inhibits Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2), a key factor in tumor growth and spread. This discovery offers a promising new avenue for developing targeted cancer therapies.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) plays a critical role in tumor angiogenesis and metastasis.
- Inhibiting VEGFR-2 is a validated strategy for cancer treatment.
- Novel inhibitors are needed to overcome limitations of existing therapies.
Purpose of the Study:
- To identify novel inhibitors of VEGFR-2 using structure-based virtual screening.
- To evaluate the binding affinity and drug-like properties of potential inhibitors.
- To validate the inhibitory activity of a lead compound against VEGFR-2.
Main Methods:
- Structure-based virtual screening (SBVS) of multiple compound databases using Glide.
- Selection of candidate compounds based on receptor fit, drug-likeness, and ADMET properties.
- Molecular mechanics/generalized Born surface area (MM/GBSA) and VEGFR-2 inhibition assays for lead compound validation.
Main Results:
- SBVS identified 22 potential hits from over 400,000 compounds.
- Hit 5 showed favorable binding free energy and stability compared to reference compounds via MM/GBSA.
- Hit 5 demonstrated VEGFR-2 inhibitory activity with an IC50 of 165.23 nM.
Conclusions:
- The identified compound (Hit 5) is a promising VEGFR-2 inhibitor.
- Further structural modifications may enhance its inhibitory potency.
- This study provides a foundation for developing new anti-cancer agents targeting VEGFR-2.
