Computational exploration of palmitoyl-protein thioesterase 1 inhibition by L. for anti-dementia treatment.

OBJECTIVES

Dementia, a growing concern globally, affects more than 55 million people-a number projected to rise to 152 million by 2050. Current medications target Alzheimer's disease, the most prevalent form of dementia. This study investigated L., a plant used in traditional Chinese medicine, as a potential inhibitor of palmitoyl-protein thioesterase 1 (PPT1), an enzyme associated with dementia.

METHODS

phytochemicals were subjected to docking against PPT1 (PDB ID: 1EH5). Docking simulations were performed in YASARA Structure with VINA scoring. Top-ranked ligands were subjected to ADMET analysis (admetlab 2.0, Protox 3.0) and PASS bioactivity prediction. Stability and reactivity were analyzed with DFT calculations (Gaussian 09), and 500 ns MD simulations (YASARA Structure, AMBER 14 force field) to assess protein-ligand complex stability. MM-PBSA was used to calculate binding free energies.

RESULTS

The docking simulations identified amentoflavone (-9.6 kcal/mol) as the top hit, followed by ferruginol and quercetin 3--pentoside. Amentoflavone formed the most interactions (19) with PPT1. toxicity analysis predicted amentoflavone and quercetin 3--pentoside to be safe, whereas ferruginol violated the Pfizer rule. The PASS server indicated a higher probability of activity for quercetin 3--pentoside (0.423) than amentoflavone (0.287) for dementia treatment. DFT calculations revealed similar electronic properties for both ligands, although amentoflavone showed slightly more favorable values. MD simulations demonstrated that amentoflavone, compared with to galantamine, had superior binding stability in the PPT1 binding pocket.

CONCLUSION

This study was aimed at identifying potential inhibitors of PPT1 from phytochemicals, given that PPT1 is a target for developing new dementia medications. Our findings identified amentoflavone as a promising candidate for further investigation. These findings warrant further research to validate this compound's potential as a PPT1 inhibitor for dementia treatment.