Abstract
Receptor tyrosine kinases (RTKs) are crucial targets in the pathway of angiogenesis and the currently used antiangiogenic drugs have limited efficiency with associated toxicity. In our continuous search for new and potent multitarget anti-angiogenic lead compounds, we have conducted in-silico interaction and inhibition studies of the selected aglycones of steroidal glycoalkaloids (GAs) and selected anti-angiogenic drugs, against the EGFR, VEGFR-1, VEGFR-2 using the AutoDock Tools 4.0 and other online bioinformatics softwares. The docking results have been interpreted in terms of binding energies (kcal/mol) and inhibition constant (mu M). In our study, aglycones [solanidine (solanid-5-en-3 beta-ol), solasodine (Solasod-5-en-3 beta-ol) and tomatidine (5 alpha-Tomatidan-3 beta-ol)] gave promising and comparable results with the antiangiogenic drugs (Gefitinib, Lapatinib, Axitinib and Motasenib). All the test aglycones expressed significant inhibition against RTKs under study, but tomatidine emerged as a most potent multi-target inhibitor of RTKs. The inhibition constant of tomatidine was observed almost 2-folds less compared to Gefitinib targeting against EGFR and 5-folds less to Axitinib, the standard drug against VEGFR-2. Moreover, these aglycones fulfilled the drug likeliness properties, when analyzed by Lipinski's Rule of Five. In addition to this, the in-silico toxicity studies of aglycones remarkably showed no mutagenecity and tumorigenecity compared to the standard drugs. Our results for the first time report that these novel aglycones of GAs may be significant lead compounds in the development of new and effective multi-target antiangiogenic drugs with the least or no toxicity. In addition, the wet lab experiments are underway to support these in-silico results.