Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives

Background: Many Natural Products, particularly phenolic compounds, have been reported to have a strong inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the key enzymes in the pathology of Alzheimer's disease (AD).

Hypothesis: Therefore, we hypothesized that some xanthahumol, naringenin, and acyl phloroglucinol derivatives (1-14) isolated from Humulus lupulus L. (hops) may have an inhibitory potential against AChE and BChE.

Methods: Inhibitory potential of compounds 1-14 were tested against AChE and BChE using ELISA microtiter assay. Different molecular docking simulations, including IFD and GOLD protocols, were implemented to verify the interactions between the ligands and the active site Amino acids and also their binding energies inside the catalytic crevices of AChE and BChE. ADME/Tox analysis were used to determine pharmacological activities of the compounds.

Results: Among them, 3‑hydroxy‑xanthohumol (IC₅₀ = 51.25 ± 0.88 µM) and xanthohumol (IC₅₀ = 71.34 ± 2.09 µM), displayed a moderate AChE inhibition in comparison to that of the reference (galanthamine, IC₅₀ = 2.52 ± 0.15 µM). In addition to 3‑hydroxy‑xanthohumol (IC₅₀ = 63.07 ± 3.76 µM) and xanthohumol (IC₅₀ = 32.67 ± 2.82 µM), 8-prenylnaringenin (IC₅₀ = 86.58 ± 3.74 µM) also showed micromolar-range inhibition against BChE (galanthamine, IC₅₀ = 46.58 ± 0.91 µM). Rest of the compounds were found to be either inactive or having inhibition below 50%. Prediction of pharmacokinetic studies suggested that all the ligands revealed acceptable drug-like profiles. Docking simulations demonstrate not only the prediction of ligand binding energies of the compounds inside the catalytic domains of the targets, but also highlight the critical Amino acids contributing to stabilizations of the ligands.

Conclusion: Our findings revealed that xanthohumol in particular could be considered as lead molecule to explore new cholinesterase inhibitors for AD.

Acyl phloroglucinol; Cholinesterase; Molecular docking; Naringenin; Xanthahumol.