Exploring Monodora myristica seed oil compounds as inhibitors of sterol O-Acyltransferase 1: implications for lipid-associated diabetic complications.

Lipid-associated complications have continued to place a heavy burden on diabetes management. This has prompted the need for the development of newer therapeutic approaches. The advent of computer-aided drug design approach which minimizes cost and time and expedite drug discovery and development, has endeared researchers towards in silico studies. The current study explores the in silico inhibitory potential of ligands from Monodora myristica seed oil against Sterol O-Acyltransferase 1 (SOAT1), an enzyme crucial to lipid metabolism and diabetic complications. Gas chromatography-mass spectrometry characterization of the seed oil revealed three prominent ligands stigmasterol, campesterol, and β-sitosterol. The interaction between these ligands and SOAT1 was studied using molecular docking simulations, revealing their close binding proximity to the enzyme's active site. The docking result indicated that the ligands bound with the SOAT1 active site at close proximity predetermined by a co-crystallized ligand (2, 2-Dimethyl-N-(2, 4, 6-trimethoxyphenyl) dodecanamide; CI-976). The binding affinity of stigmasterol was - 10.3 kcal/mol; campesterol, - 12.6 kcal/mol and β-sitosterol, - 10.3 kcal/mol while that of the standard inhibitor (CI-976) was - 8.2 kcal/mol at the binding pocket of the protein. Also, the ligands exhibited more profound drug-like prediction properties than the co-crystallised ligand (stigmasetrol, - 0.62; campesterol, - 0.59; β sitosterol, - 0.78 and CI-976, - 0.19). Whereas campesterol and stigmasterol exhibited a joint highest binding affinity to the protein, β sitosterol demonstrated a higher drug-like properties compared to CI-976. The result potentiates sterols from Monodora myristica seed oil as probable drug candidates against lipid-associated diabetes complication. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00502-6.