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Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives.
Phytomedicine. 2018 Mar 15; 42:25-33.P

Abstract

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.

Authors+Show Affiliations

Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara 06330, Turkey. Electronic address: iorhan@gazi.edu.tr.Institute of Soil Science and Plant Cultivation, State Research Institute, Czartoryskich 8, Pulawy 24-100, Poland.Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara 06330, Turkey.Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul 34349, Turkey.Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul 34349, Turkey.Institute of Soil Science and Plant Cultivation, State Research Institute, Czartoryskich 8, Pulawy 24-100, Poland.Institute of Soil Science and Plant Cultivation, State Research Institute, Czartoryskich 8, Pulawy 24-100, Poland.Institute of Soil Science and Plant Cultivation, State Research Institute, Czartoryskich 8, Pulawy 24-100, Poland.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29655693

Citation

Orhan, Ilkay Erdogan, et al. "Molecular Modeling and in Vitro Approaches Towards Cholinesterase Inhibitory Effect of some Natural Xanthohumol, Naringenin, and Acyl Phloroglucinol Derivatives." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 42, 2018, pp. 25-33.
Orhan IE, Jedrejek D, Senol FS, et al. Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives. Phytomedicine. 2018;42:25-33.
Orhan, I. E., Jedrejek, D., Senol, F. S., Salmas, R. E., Durdagi, S., Kowalska, I., Pecio, L., & Oleszek, W. (2018). Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 42, 25-33. https://doi.org/10.1016/j.phymed.2018.03.009
Orhan IE, et al. Molecular Modeling and in Vitro Approaches Towards Cholinesterase Inhibitory Effect of some Natural Xanthohumol, Naringenin, and Acyl Phloroglucinol Derivatives. Phytomedicine. 2018 Mar 15;42:25-33. PubMed PMID: 29655693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular modeling and in vitro approaches towards cholinesterase inhibitory effect of some natural xanthohumol, naringenin, and acyl phloroglucinol derivatives. AU - Orhan,Ilkay Erdogan, AU - Jedrejek,Dariusz, AU - Senol,F Sezer, AU - Salmas,Ramin Ekhteiari, AU - Durdagi,Serdar, AU - Kowalska,Iwona, AU - Pecio,Lukasz, AU - Oleszek,Wieslaw, Y1 - 2018/03/06/ PY - 2017/10/27/received PY - 2018/01/07/revised PY - 2018/03/04/accepted PY - 2018/4/16/entrez PY - 2018/4/16/pubmed PY - 2018/8/14/medline KW - Acyl phloroglucinol KW - Cholinesterase KW - Molecular docking KW - Naringenin KW - Xanthahumol SP - 25 EP - 33 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 42 N2 - 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. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/29655693/Molecular_modeling_and_in_vitro_approaches_towards_cholinesterase_inhibitory_effect_of_some_natural_xanthohumol_naringenin_and_acyl_phloroglucinol_derivatives_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(18)30040-0 DB - PRIME DP - Unbound Medicine ER -