Discovery of novel bioactive compounds in Catharanthus roseus exhibiting anti-angiogenic activity against VEGFR-2 TKD for Glioblastoma tumor growth suppression

The progression of Glioblastoma (GBM) relies heavily on angiogenesis, the formation of new blood vessels, facilitated by proangiogenic factors like vascular endothelial growth factor (VEGF) within the tumor microenvironment. VEGF interacts primarily with its receptor VEGFR-2 (VEGF receptor-2), making it a key target for anti-angiogenic therapy. Existing anti-angiogenic agents, while effective, often pose cardiovascular risks, necessitating the exploration of safer alternatives. Plant-based compounds, including those from Catharanthus roseus, show promise in this regard. Despite the known anti-angiogenic activity in C. roseus extracts, a comprehensive investigation into its phytoconstituents and their anti-angiogenic potential is lacking. This study aims to fill this gap by employing in silico methods to screen for safe and novel anti-angiogenic compounds from C. roseus targeting VEGFR-2 tyrosine kinase domain (VEGFR-2 TKD). Utilizing molecular docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) tools, (16R)-Dihydrositsirikine emerges as a promising candidate, exhibiting drug-like properties, non-toxicity, and binding affinity of -7.2 kcal/mol to ATP binding site on VEGFR-2 TKD, greater than that of the ATP (-6.6 Kcal/mol). Molecular Dynamics (MD) simulation further confirms the stability of the (16R)-Dihydrositsirikine-VEGFR-2 TKD complex, supported by good hydrogen-bonding (H-bonding). Free energy calculations via MM-GBSA corroborate the favourable binding free energy. In conclusion, this study highlights the potential of (16R)-Dihydrositsirikine as a safe and effective anti-angiogenic agent for GBM therapy, paving the way for future preclinical and clinical investigations.