Related Experiment Video
Updated: May 31, 2025
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
Computer-assisted discovery of natural inhibitors for platelet-derived growth factor alpha as novel therapeutics for
Hira Khalid1, Farah Sattar1, Iqra Ahmad1
1Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan.
Abstract:
Platelet-derived growth factor alpha (PDGFRA) plays a significant role in various malignant tumors. PDGFRA expression boosts thyroid cancer cell proliferation and metastasis. Radiorefractory thyroid cancer is poorly differentiated, very aggressive, and resistant to radioiodine therapy. Thus, novel anticancer drugs that inhibit its metastasis are urgently required. In this context, we proposed the PDGFRA inhibitors by an optimized structure-based drug design approach. We performed a virtual screening of metabolites derived from anticancer medicinal plants (Swertia chirayita, Myristica fragrans, and Datura metel) and successfully identified seven hits, namely cis-Grossamide K, Daturafoliside O, N-cis-feruloyltyramine, Maceneolignan H, Erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4, 5-trimethoxyphenyl) propan-1, 3-diol, Myrifralignan C, and stigmasteryl-3-O-β-glucoside as potential PDGFRA inhibitors. Not only the top 7 hits exhibited higher docking scores in docking simulation but also optimal drug-likeness and non-toxic profiles in pharmacokinetics analysis among 119 compounds. Our top hits are non-mutagenic, can cross the blood-brain barrier, and inhibit p-glycoprotein, while the N-cis-feruloyltyramine has the potential to become a lead compound. The protein-ligand stability of the top 3 hits, namely cis-Grossamide K, Daturafoliside O, and N-cis-feruloyltyramine, and their interactions at the potential binding site of target protein were confirmed through molecular dynamic simulations. We also analyzed pharmacophoric features for stable binding in the PDGFRA active site. These drug candidates were further characterized to predict their biological activity spectra in the human body and medicinal characteristics to know their extensive behavior in laboratory testing. This study necessitates the in-vitro and in-vivo studies to confirm the potential of our hits for the discovery of novel therapeutics against the thyroid cancer.
Insights
Researchers identified potential new drugs targeting PDGFRA to inhibit thyroid cancer metastasis. Natural compounds from medicinal plants show promise as non-toxic, drug-like inhibitors for further therapeutic development.
Area of Science:
- Computational chemistry and drug discovery
- Oncology and cancer therapeutics
- Pharmacology and medicinal chemistry
Background:
- Platelet-derived growth factor alpha (PDGFRA) is implicated in thyroid cancer proliferation and metastasis.
- Radiorefractory thyroid cancer is aggressive and requires novel therapeutic strategies to combat metastasis.
- There is an urgent need for new anticancer drugs targeting PDGFRA to improve treatment outcomes.
Purpose of the Study:
- To identify potential PDGFRA inhibitors using structure-based drug design.
- To screen natural compounds from medicinal plants for anticancer activity against thyroid cancer.
- To evaluate the drug-likeness and safety profiles of identified compounds.
Main Methods:
- Structure-based virtual screening of 119 metabolites from Swertia chirayita, Myristica fragrans, and Datura metel.
- Molecular docking simulations to assess binding affinity to PDGFRA.
- Pharmacokinetic analysis for drug-likeness and toxicity prediction.
- Molecular dynamic simulations to confirm protein-ligand stability and interactions.
Main Results:
- Seven potential PDGFRA inhibitors were identified, including cis-Grossamide K, Daturafoliside O, and N-cis-feruloyltyramine.
- The top hits demonstrated favorable docking scores, optimal drug-likeness, and non-toxic profiles.
- N-cis-feruloyltyramine emerged as a potential lead compound with promising characteristics for further development.
- Molecular dynamics confirmed the stability and binding interactions of the top three compounds.
Conclusions:
- The identified natural compounds show significant potential as novel PDGFRA inhibitors for thyroid cancer therapy.
- Further in vitro and in vivo studies are warranted to validate these findings and advance drug discovery.
- This study highlights the value of natural products in developing targeted anticancer therapeutics.
Related Concept Videos
01:20Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
01:27Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...