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A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Structure-Activity Relationship Studies on VEGFR2 Tyrosine Kinase Inhibitors for Identification of Potential Natural
Meenakshi Verma1,2, Aqib Sarfraz3, Inamul Hasan3
1Plant Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow 226015 (Uttar Pradesh), India.
Background:
Over-expression of Vascular Endothelial Growth Factor Receptors (VEGFRs) leads to the hyperactivation of oncogenes. For inhibition of this hyperactivation, the USA Food Drug Administration (FDA) has approved many drugs that show adverse effects, such as hypertension, hypothyroidism, etc. There is a need to discover potent natural compounds that show minimal side effects. In the present study, we have taken structurally diverse known VEGFR2 inhibitors to develop a Quantitative Structure-Activity Relationship (QSAR) model and used this model to predict the inhibitory activity of natural compounds for VEGFR2.
Methods:
The QSAR model was developed through the forward stepwise Multiple Linear Regression (MLR) method. A developed QSAR model was used to predict the inhibitory activity of natural compounds. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessment and molecular docking studies were performed. The binding stability of the natural compounds with VEGFR2 was elucidated through Molecular Dynamics (MD) simulation.
Results:
The developed QSAR model against VEGFR2 showed the regression coefficient of the training dataset (r2) as 0.81 and the external regression coefficient of the test dataset (r2 test) 0.71. Descriptors, viz., electro-topological state of potential hydrogen bonds (maxHBint2, nHBint6), atom types (minssNH), maximum topological distance matrix (SpMAD_Dt), and 2D autocorrelation (ATSC7v), have been identified. Using this model, 14 natural compounds have been selected that have shown inhibitory activity for VEGFR2, of which six natural compounds have been found to possess a strong binding affinity with VEGFR2. In MD simulation, four complexes have shown binding stability up to 50ns.
Conclusion:
The developed QSAR model has identified 5 conserved activity-inducing physiochemical properties, which have been found to be correlated with the anticancer activity of the nonidentical ligand molecules bound with the VEGFR2 kinase. Lavendustin_A, 3'-O-acetylhamaudol, and arctigenin have been obtained as possible lead natural compounds against the VEGFR2 kinase.
Insights
This study developed a Quantitative Structure-Activity Relationship (QSAR) model to identify natural compounds as potential VEGFR2 inhibitors. Several natural compounds, including Lavendustin_A, showed promising inhibitory activity and binding affinity, offering alternatives to existing drugs.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Vascular Endothelial Growth Factor Receptors (VEGFRs) over-expression drives oncogene hyperactivation.
- Approved VEGFR inhibitors cause adverse effects like hypertension and hypothyroidism.
- There is a critical need for novel natural compounds with minimal side effects.
Purpose of the Study:
- To develop a Quantitative Structure-Activity Relationship (QSAR) model for predicting VEGFR2 inhibitory activity.
- To identify potent natural compounds as potential VEGFR2 inhibitors.
- To evaluate the binding affinity and stability of natural compounds with VEGFR2.
Main Methods:
- Quantitative Structure-Activity Relationship (QSAR) model development using Multiple Linear Regression (MLR).
- Prediction of inhibitory activity for natural compounds using the QSAR model.
- Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessment, molecular docking, and Molecular Dynamics (MD) simulations.
Main Results:
- A QSAR model with high predictive accuracy (r2=0.81, r2 test=0.71) was developed.
- Key descriptors influencing VEGFR2 inhibition were identified.
- Fourteen natural compounds exhibited VEGFR2 inhibitory activity, with six showing strong binding affinity.
- MD simulations confirmed binding stability for four complexes up to 50ns.
Conclusions:
- The QSAR model identified five conserved physiochemical properties correlated with anticancer activity against VEGFR2.
- Lavendustin_A, 3'-O-acetylhamaudol, and arctigenin emerged as promising lead natural compounds.
- These findings suggest potential natural product-based therapeutic strategies for VEGFR2-driven cancers.
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