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

Abstract

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.

New Diacetic Acids Containing Quinazolin‐4(3H)‐one: Synthesis, Characterization, Anticholinergic Properties, DFT Analysis and Molecular Docking Studies

“…The BChE consists of subunits; a catalytic triad, an anionic site, a peripheral anionic site, an oxyanion hole, and an acyl pocket [34] . The catalytic triad contains GLU325, SER198, and HIS438.…”

“…The BChE consists of subunits; a catalytic triad, an anionic site, a peripheral anionic site, an oxyanion hole, and an acyl pocket. [34] The catalytic triad contains GLU325, SER198, and HIS438. Compound 14 interacted with SER198 and HIS438 via hydrogen bonds, while compound 5 showed hydrophobic π-π interaction with HIS438.…”

“…The AChE enzyme consists of four subunits: the esteratic site, peripheral anionic site, oxyanion hole, and acyl pocket. [34] The esteratic site hydrolyzes acetylcholine and contains the catalytic triad (SER203, HIS447, and GLU334). Compound 2 interacts with SER203, and compound 14 interacts with HIS447 through hydrogen bonds.…”

Alzheimer’s Disease: Pathogenesis, Hypothesis and Management

“…Currently, the medications available for AD provide only modest and transient benefits to a subset of patients. Acetylcholinesterase inhibitors and memantine are two commonly prescribed medications for patients with mild-moderate AD ( Ji et al, 2022). Acetylcholinesterase inhibitors increased the level of acetylcholine neurotransmitter that is involved in learning and memory processes.…”