AI fragmentation-based optimization of Sorafenib derivatives targeting VEGFR2 for angiogenesis-related pathologies: a structure-based in-silico study

Vascular endothelial growth factor receptor 2 (VEGFR2) is a central regulator of angiogenesis and endothelial signaling and represents a validated therapeutic target in multiple angiogenesis-associated pathologies. Sorafenib is a clinically used multi-kinase inhibitor with VEGFR2 activity; however, its scaffold is limited by suboptimal pharmacokinetics and toxicity liabilities. In present investigation, we have engineered and evaluated Sorafenib derivatives following artificial intelligence through structure-based drug design (SBDD) and fragments-based drug design (FBDD). Out of twenty derivatives generated, the most efficient derivative, named AI- Fragmented Derivative 7 (Grow), displayed higher binding affinity for the VEGFR2 when compared to Sorafenib. Molecular dynamics simulation was performed to confirm structural stability for the VEGFR2-AI lead complex. Density Functional Theory (DFT) computations showed this by producing a lower HOMO-LUMO energy gap for lead than Sorafenib. Pharmacokinetic profiling (ADMET) associated the compound with enhanced aqueous solubility and absence of hepatotoxicity was predicted compared to the hepatotoxic profile of Sorafenib. Free energy estimations with MM/GBSA and MM/PBSA further supported the thermodynamic properties of derivative 7. Collectively, these computational results support Derivative 7 as a promising VEGFR2-directed lead candidate for angiogenesis-associated diseases; however, all conclusions are based on in silico modeling and require experimental validation of potency, selectivity, and safety.

In silico; Angiogenesis; DFT; Molecular dynamics; Sorafenib; VEGFR2.