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Repurposing Antipsychotic Agents Against Targets of Angiogenesis Pathways for Cancer Therapy: An in-silico Approach
Rahmon Kanmodi1, Habeeb Bankole1, Regina Oddiri1
1Department of Biochemistry, Faculty of Science, Lagos State University, Lagos, Nigeria.
Background:
Antipsychotics interfere with virtually all hallmarks of cancer, including angiogenesis. Vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth receptors (PDGFRs) play crucial roles in angiogenesis and represent targets of many anti-cancer agents. We assessed and compared the binding effects of antipsychotics and receptor tyrosine kinase inhibitors (RTKIs) on VEGFR2 and PDGFRα.
Methods:
FDA-approved antipsychotics and RTKIs were retrieved from DrugBank. VEGFR2 and PDGFRα structures were obtained from Protein Data Bank and loaded on Biovia Discovery Studio software to remove nonstandard molecules. Molecular docking was carried out using PyRx and CBDock to determine the binding affinities of protein-ligand complexes.
Results:
Risperidone exerted the highest binding effect on PDGFRα (-11.0 Kcal/mol) as compared to other antipsychotic drugs and RTKIs. Risperidone also demonstrated a stronger binding effect on VEGFR2 (-9.6 Kcal/mol) than the RTKIs, pazopanib (-8.7 Kcal/mol), axitinib (-9.3 Kcal/mol), vandetanib (-8.3 Kcal/mol), lenvatinib ( -7.6 Kcal/mol) and sunitinib (-8.3 Kcal/mol). Sorafenib (an RTKI), however, exhibited the highest VEGFR2 binding affinity of -11.7 Kcal/mol.
Conclusion:
Risperidone's superior binding affinity with PDGFRα when compared to all reference RTKIs and antipsychotic drugs, as well as its stronger binding effect on VEGFR2 over the RTKIs, sunitinib, pazopanib, axitinib, vandetanib, and lenvatinib, imply that it could be repurposed to inhibit angiogenic pathways and subjected to pre-clinical and clinical trials for cancer therapy.
Insights
The antipsychotic risperidone shows strong binding to cancer targets PDGFRα and VEGFR2, suggesting potential for repurposing in cancer therapy. Further trials are recommended to explore its anti-angiogenic properties.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Antipsychotics can impact cancer hallmarks like angiogenesis.
- Vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth receptors (PDGFRs) are key targets in anti-cancer drug development.
- This study compares the binding affinities of antipsychotics and receptor tyrosine kinase inhibitors (RTKIs) to VEGFR2 and PDGFRα.
Purpose of the Study:
- To assess and compare the binding effects of antipsychotics and RTKIs on VEGFR2 and PDGFRα.
- To identify potential novel anti-cancer applications for existing antipsychotic medications.
Main Methods:
- Utilized FDA-approved antipsychotics and RTKIs from DrugBank.
- Obtained VEGFR2 and PDGFRα structures from the Protein Data Bank.
- Performed molecular docking using PyRx and CBDock to determine binding affinities.
Main Results:
- Risperidone exhibited the highest binding affinity for PDGFRα (-11.0 Kcal/mol) among all tested drugs.
- Risperidone showed stronger binding to VEGFR2 (-9.6 Kcal/mol) than several RTKIs, including pazopanib, axitinib, vandetanib, lenvatinib, and sunitinib.
- Sorafenib, an RTKI, had the highest VEGFR2 binding affinity (-11.7 Kcal/mol).
Conclusions:
- Risperidone's significant binding affinity to PDGFRα and VEGFR2 suggests its potential for repurposing as an anti-angiogenic cancer therapeutic.
- The findings support further pre-clinical and clinical investigation of risperidone for cancer therapy.
- This research highlights the potential of repurposing existing drugs for novel therapeutic applications.
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