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Anticholinesterase Inhibition, Drug-Likeness Assessment, and Molecular Docking Evaluation of Milk Protein-Derived Opioid Peptides for the Control of Alzheimer’s Disease

1
Department of Food Science, University of Otago, Dunedin 9054, New Zealand
2
Department of Management, University of Otago, Dunedin 9054, New Zealand
3
School of Biological Sciences, The University of Auckland, Auckland 1142, New Zealand
*
Author to whom correspondence should be addressed.
Academic Editor: Daniela Barile
Dairy 2022, 3(3), 422-437; https://doi.org/10.3390/dairy3030032
Received: 21 April 2022 / Revised: 18 June 2022 / Accepted: 20 June 2022 / Published: 23 June 2022
The drug-likeness and pharmacokinetic properties of 23 dairy-protein-derived opioid peptides were studied using SwissADME and ADMETlab in silico tools. All the opioid peptides had poor drug-like properties based on violations of Lipinski’s rule-of-five. Moreover, prediction of their pharmacokinetic properties showed that the peptides had poor intestinal absorption and bioavailability. Following this, two well-known opioid peptides (βb-casomorphin-5, βb-casomorphin-7) from A1 bovine milk and caffeine (positive control) were selected for in silico molecular docking and in vitro inhibition study with two cholinesterase enzyme receptors important for the pathogenesis of Alzheimer’s disease. Both peptides showed higher binding free energies and inhibitory activities to butyrylcholinesterase (BChE) than caffeine, but in vitro binding energy values were lower than those from the docking model. Moreover, the two casomorphins had lower inhibitory properties against acetylcholinesterase (AChE) than caffeine, although the docking model predicted the opposite. At 1 mg/mL concentrations, βb-casomorphin-5 and βb-casomorphin-7 showed promising results in inhibiting both cholinesterases (i.e., respectively 34% and 43% inhibition of AChE, and 67% and 81% inhibition of BChE). These dairy-derived opioid peptides have the potential to treat Alzheimer’s disease via cholinesterase inhibition. However, appropriate derivatization may be required to improve their poor predicted intestinal absorption and bioavailability. View Full-Text
Keywords: casomorphins; opioid peptides; cholinesterase inhibitors; molecular docking; bioinformatics; Alzheimer’s disease casomorphins; opioid peptides; cholinesterase inhibitors; molecular docking; bioinformatics; Alzheimer’s disease
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MDPI and ACS Style

Ji, D.; Ma, J.; Dai, J.; Xu, M.; Harris, P.W.R.; Brimble, M.A.; Agyei, D. Anticholinesterase Inhibition, Drug-Likeness Assessment, and Molecular Docking Evaluation of Milk Protein-Derived Opioid Peptides for the Control of Alzheimer’s Disease. Dairy 2022, 3, 422-437. https://doi.org/10.3390/dairy3030032

AMA Style

Ji D, Ma J, Dai J, Xu M, Harris PWR, Brimble MA, Agyei D. Anticholinesterase Inhibition, Drug-Likeness Assessment, and Molecular Docking Evaluation of Milk Protein-Derived Opioid Peptides for the Control of Alzheimer’s Disease. Dairy. 2022; 3(3):422-437. https://doi.org/10.3390/dairy3030032

Chicago/Turabian Style

Ji, Dawei, Jingying Ma, Junyi Dai, Min Xu, Paul W.R. Harris, Margaret A. Brimble, and Dominic Agyei. 2022. "Anticholinesterase Inhibition, Drug-Likeness Assessment, and Molecular Docking Evaluation of Milk Protein-Derived Opioid Peptides for the Control of Alzheimer’s Disease" Dairy 3, no. 3: 422-437. https://doi.org/10.3390/dairy3030032

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