Integrated Computational Evaluation of Natural Compounds as Potential S1PR2 Modulators in Aortic Valve Stenosis

• Therapeutic target : S1PR2 is implicated in aortic valve stenosis and represents a viable drug target. • Computational approach : Cardiovascularly relevant natural products were screened using integrated molecular modeling techniques. • Key findings : Several compounds exhibited strong and stable S1PR2 binding with favorable drug-likeness and ADMET profiles. • Implications : Natural products represent promising scaffolds for S1PR2-targeted drug development. Sphingosine-1-phosphate receptor 2 (S1PR2) is considered as a key factor to the molecular pathology of aortic valve stenosis (AVS), where excessive sphingosine-1-phosphate signaling is associated with disease progression. Accordingly, modulation of S1PR2 represents an attractive therapeutic avenue for controlling the AVS. In the present study, a selected set of natural compounds with reported cardiovascular effects was explored via an integrated in silico strategy to identify potential S1PR2 inhibitors. Docking analyses followed by molecular dynamics simulations exhibited stable ligand-receptor complexes and favorable interaction patterns for several candidates within the S1PR2 binding pocket, suggesting strong inhibitory potential. A structure-based pharmacophore model was subsequently constructed to determine the essential functional features required for S1PR2 modulation, leading to the prioritization of compounds such as digoxin, ginsenoside Rb1, menaquinone-7, hesperidin, and naringin. Further computational investigations, including density functional theory calculations, drug-likeness analysis, and ADME/Tox predictions, indicated that some of these natural products display favorable electronic properties, acceptable pharmacokinetic behavior, and improved safety profiles when compared with the reported S1PR2 antagonist JTE-013. Overall, this study identifies several natural compounds as promising S1PR2-targeted candidates and provides a computational foundation for their experimental validation.