Natural P2Y12 inhibitors as antiplatelet leads: A multi-tool in silico study

Context: Uncontrolled platelet aggregation underlies thrombotic disorders and remains a major contributor to cardiovascular mortality. The platelet-specific P2Y₁₂ receptor is a validated target for antithrombotic therapy. Aims: To identify natural P2Y₁₂ antagonists via an integrated in silico workflow. Methods: Pharmacophore modeling (AAARR hypothesis), virtual screening of 449,008 SN3 natural compounds, Glide docking (HTVS→SP→XP), MM-GBSA rescoring, and 100 ns molecular dynamics simulations were employed. Results: Three tannin derivatives (SN0208535, SN0257464, SN0084030) exhibited superior XP docking scores (≤ –15.0 kcal/mol), favorable MM-GBSA energies (≤ –84 kcal/mol), and stable binding throughout MD (RMSD ≤ 2.5 Å). Conclusions: These compounds have promising potential for further development as new antiplatelet candidates.