3D physiologically-informed deep learning for drug discovery of a novel vascular endothelial growth factor receptor-2 (VEGFR2).

Angiogenesis is an essential process in tumorigenesis, tumor invasion, and metastasis, and is an intriguing pathway for drug discovery. Targeting vascular endothelial growth factor receptor 2 (VEGFR2) to inhibit tumor angiogenic pathways has been widely explored and adopted in clinical practice. However, most drugs, such as the Food and Drug Administration -approved drug axitinib (ATC code: L01EK01), have considerable side effects and limited tolerability. Therefore, there is an urgent need for the development of novel VEGFR2 inhibitors. In this study, we propose a novel strategy to design potential candidates targeting VEGFR2 using three-dimensional (3D) deep learning and structural modeling methods. A geometric-enhanced molecular representation learning method (GEM) model employing a graph neural network (GNN) as its underlying predictive algorithm was used to predict the activity of the candidates. In the structural modeling method, flexible docking was performed to screen data with high affinity and explore the mechanism of the inhibitors. Small -molecule compounds with consistently improved properties were identified based on the intersection of the scores obtained from both methods. Candidates identified using the GEM-GNN model were selected for in silico modeling using molecular dynamics simulations to further validate their efficacy. The GEM-GNN model enabled the identification of candidate compounds with potentially more favorable properties than the existing drug, axitinib, while achieving higher efficacy.