Farnesiferol B and kamolonol isolated from Ferula assa-foetida are potent BACE1 inhibitors with neuroprotective effects

Five compounds were isolated from Ferula assa-foetida and their BACE1 inhibitory activities were evaluated. Farnesiferol B and kamolonol showed potent BACE1 inhibitory activity with IC50 values of 8.11 and 1.00 µM and competitive inhibition patterns against BACE1, with Ki values of 6.51 and 0.41µM, respectively. In silico pharmacokinetics showed that farnesiferol B was predicted to have high gastrointestinal absorption and blood-brain barrier permeability. In cell studies, farnesiferol B and kamolonol were nontoxic to normal Madin-Darby canine kidney and neuroblastoma SH-SY5Y cells, and both showed protective effects on SH-SY5Y cells for Aβ42-induced neurotoxicity. In molecular docking simulations, we found that the efficacy of the compounds may be related to their interaction with the flap region and hydrogen bonding with ARG368. In addition, molecular dynamics simulation of kamolonol showed the ligand maintained its stability in interaction with the loop residues. These results show that farnesiferol B and kamolonol are potent BACE1 inhibitors with neuroprotective effects, suggesting that they are potential candidates for the treatment of neurodegenerative disorders, such as Alzheimer’s disease.

Publikationsverlauf

Eingereicht: 13. April 2025

Angenommen nach Revision: 25. August 2025

Accepted Manuscript online:
25. August 2025