Repurposing Antipsychotic Agents Against Targets of Angiogenesis Pathways for Cancer Therapy: An in-silico Approach.

Abstract

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.