In silico identification and evaluation of a novel GDF15 inhibitor for coronary artery disease

Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, plays a critical role in cardiovascular homeostasis and is markedly elevated in coronary artery disease (CAD). However, despite its pathological relevance, direct small-molecule inhibitors targeting GDF15 remain largely unexplored in the context of atherosclerosis. This study aimed to identify potential GDF15 modulators using an integrated computational drug discovery approach. The crystal structure of GDF15 (PDB ID: 5VT2) was retrieved from the RCSB PDB, and its druggable pocket was characterized using CASTp. A diverse chemical space comprising FDA-approved drugs, natural products, cardiovascular agents, TGF-β pathway inhibitors, and investigational molecules was screened through molecular docking. Docking scores ranged up to − 8.0 kcal/mol, with Obacunone and Sotrastaurine demonstrating the strongest affinities and forming stable interactions with key binding-site residues including ALA55, ASN56, VAL79, PRO80, ALA81, SER82, TYR83, ASP102, ASP103, HIS110, and ILE112. Top candidates exhibited favorable pharmacokinetic behavior based on SwissADME and pkCSM analyses. Molecular dynamics simulations further revealed that both ligands maintained stable and compact GDF15–ligand complexes throughout the simulation period, with Obacunone displaying minimal conformational fluctuations and superior structural integrity. Overall, this study highlights Obacunone as a promising small-molecule inhibitor capable of modulating GDF15 activity in CAD. These findings provide a foundational computational framework that supports subsequent in vitro and in vivo validation toward therapeutic development.