In silico discovery of alkaloids as VEGFR-2 inhibitors with favorable toxicity profiles: insights from molecular dynamics and MM/GBSA.

Aberrant angiogenesis mediated by VEGFR-2 is a hallmark of aggressive cancers and a validated therapeutic target. Although clinical tyrosine kinase inhibitors (TKIs) such as sorafenib have shown efficacy, their use is often limited by significant toxicity. In this study, we employed an integrated in silico approach to identify novel VEGFR-2 inhibitors among alkaloids from Brazilian biodiversity, aiming for high affinity and improved safety profiles. A curated library of alkaloids from the NuBBEDB was screened by molecular docking, and top candidates were subjected to a rigorous evaluation pipeline, including MM/GBSA rescoring, toxicity and ADME prediction, and in-depth post-dynamic analyses of 300 ns simulations, such as hydrogen bond analysis and principal component analysis (PCA). The alkaloids NuBBE_306 and NuBBE_456 emerged with strong binding affinities (ΔGbind = - 50.24 and - 47.37 kcal/mol, respectively) and favorable safety and ADME profiles compared to sorafenib. Crucially, the dynamic analyses revealed that NuBBE_456 stands out by maintaining a network of persistent hydrogen bonds and by mimicking the free energy landscape of sorafenib, stabilizing the same inhibited kinase conformation. These findings identify NuBBE_456 as an exceptional lead candidate, combining robust affinity, dynamic stability, and low predicted toxicity, warranting its prioritization for experimental validation. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00410-9.