Anticholinesterase Inhibition, Drug-Likeness Assessment, and Molecular Docking Evaluation of Milk Protein-Derived Opioid Peptides for the Control of Alzheimer’s Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation and Characterization of In Silico Opioid Peptides Used in This Study
2.2. In Silico Drug-Likeness Assessment of Opioid Peptides
2.3. Molecular Docking of Peptides
2.4. Peptides Synthesis, Purification, and Characterization
2.4.1. Synthesis of β-casomorphin 5
2.4.2. Synthesis of β-casomorphin 7
2.4.3. Peptide Characterization
2.5. In Vitro Anticholinesterase Inhibitory Enzyme Activity of Casomorphins
3. Results and Discussion
3.1. Hypothesis and Justification
3.2. Drug-Likeness and Related Properties of Opioid Peptides
3.2.1. In Silico Evaluation of Physicochemical Properties of the Opioid Peptides
3.2.2. In Silico Evaluation of the Pharmacokinetic Properties of the Opioid Peptides
3.3. Molecular Docking of Peptides to Substrates
3.4. In Vitro Cholinesterase Inhibition by β-casomorphin-5 and β-casomorphin-7
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Number | Opioid Peptide | Source | Sequence |
---|---|---|---|
1 | βb-casomorphin-4 | bovine milk β-casein | YPFP |
2 | βb-casomorphin-5 | bovine milk β-casein | YPFPG |
3 | βb-casomorphin-6 | bovine milk β-casein | YPFPGP |
4 | βb-casomorphin-7 | bovine milk β-casein | YPFPGPI |
5 | βb-casomorphin-8 (A1) | bovine milk A1 β-casein | YPFPGPIH |
6 | βb-casomorphin-8 (A2) | bovine milk A2 β-casein | YPFPGPIP |
7 | neocasomorphin-6 | bovine milk β-casein | YPVEPF |
8 | αb-casein exorphin (1-7) | bovine milk α-casein | RYLGYLE |
9 | αb-casein exorphin (2-7) | bovine milk α-casein | YLGYLE |
10 | casoxin A | bovine milk κ-casein | YPSYGLN |
11 | casoxin B | bovine milk κ-casein | YPYY |
12 | casoxin C | bovine milk κ-casein | YIPIQYVLSR |
13 | α-lactorphin | bovine/human milk α-lactalbumin | YGLF-NH2 |
14 | βb-lactorphin | bovine milk β-lactoglobulin | YLLF-NH2 |
15 | lactoferroxin A | bovine/human milk lactoferrin | YLGSGY-OCH3 |
16 | lactoferroxin B | bovine/human milk lactoferrin | RYYGY-OCH3 |
17 | lactoferroxin C | bovine/human milk lactoferrin | KYLGPQY-OCH3 |
18 | βh-casomorphin-4 | human milk β-casein | YPFV |
19 | βh-casomorphin-5 | human milk β-casein | YPFVE |
20 | βh-casomorphin-7 | human milk β-casein | YPFVEPI |
21 | βh-casomorphin-8 | human milk β-casein | YPFVEPIP |
22 | casoxin D | human milk α-casein | YVPFPPF |
23 | αh-casomorphin | human milk α-casein | YVPFP |
Rule-of-5 | HIA (+/−) | Pgp-Substrate (Y/N) | BBB (+/−) | CYP3A4-Inhibitor (Y/N) | ||||||
---|---|---|---|---|---|---|---|---|---|---|
No. | Molecular weight | HBD | HBA | LogP | Solubility (µg/mL) | |||||
Optimal range | ≤500 | ≤5 | ≤10 | ≤5 | >10 | |||||
1 | βb-casomorphin-4 | 523 | 4 | 6 | 1.056 | 158 | (−) | N | (−) | N |
2 | βb-casomorphin-5 | 580 | 5 | 7 | 0.172 | 341 | (−) | Y | (−) | Y |
3 | βb-casomorphin-6 | 677 | 5 | 8 | 0.163 | 300 | (−) | Y | (−) | Y |
4 | βb-casomorphin-7 | 790 | 6 | 9 | 0.694 | 217 | (−) | Y | (−) | Y |
5 | βb-casomorphin-8 (A1) | 927 | 8 | 11 | 0.145 | 272 | (−) | Y | (−) | Y |
6 | βb-casomorphin-8 (A2) | 887 | 6 | 10 | 0.685 | 216 | (−) | Y | (−) | Y |
7 | neocasomorphin-6 | 751 | 7 | 9 | 0.547 | 245 | (−) | Y | (−) | Y |
8 | αb-casein exorphin (1-7) | 913 | 14 | 12 | −0.945 | 438 | (−) | Y | (+) | Y |
9 | αb-casein exorphin (2-7) | 757 | 10 | 10 | 0.307 | 374 | (−) | Y | (+) | N |
10 | casoxin A | 813 | 11 | 12 | −2.745 | 415 | (−) | Y | (−) | Y |
11 | casoxin B | 605 | 7 | 8 | 1.204 | 159 | (−) | N | (−) | N |
12 | casoxin C | 1251 | 17 | 16 | −1.52 | 331 | (−) | Y | (−) | Y |
13 | α-lactorphin | 498 | 6 | 6 | 0.122 | 255 | (−) | Y | (+) | Y |
14 | βb-lactorphin | 554 | 6 | 6 | 1.537 | 123 | (+) | Y | (+) | N |
15 | lactoferroxin A | 673 | 9 | 11 | −1.891 | 430 | (−) | Y | (−) | N |
16 | lactoferroxin B | 735 | 10 | 11 | −1.044 | 257 | (−) | Y | (+) | Y |
17 | lactoferroxin C | 882 | 10 | 13 | −1.13 | 380 | (−) | Y | (−) | Y |
18 | βh-casomorphin-4 | 525 | 5 | 6 | 1.206 | 162 | (−) | Y | (−) | Y |
19 | βh-casomorphin-5 | 654 | 7 | 8 | 0.556 | 237 | (−) | Y | (−) | Y |
20 | βh-casomorphin-7 | 864 | 8 | 10 | 1.077 | 210 | (−) | Y | (−) | Y |
21 | βh-casomorphin-8 | 961 | 8 | 11 | 1.068 | 207 | (−) | Y | (−) | Y |
22 | casoxin D | 866 | 6 | 19 | 1.915 | 125 | (−) | Y | (−) | Y |
23 | αh-casomorphin | 622 | 5 | 7 | 1.197 | 199 | (−) | Y | (−) | Y |
24 | Caffeine | 194 | 6 | 0 | −1.029 | 11,435 | (+) | N | (+) | N |
AChE | BChE | |||
---|---|---|---|---|
Ligand | Binding free energy (kcal/mol) | Estimated Ki (μM) | Binding free energy (kJ/mol) | Estimated Ki (μM) |
βb-casomorphin-5 | −14.6 | −14.8 | ||
βb-casomorphin-7 | −10.1 | 0.04 | −14.4 | |
Caffeine | −6.7 | 12.12 | −6.5 | 16.99 |
βb-casomorphin-5 | βb-casomorphin-7 | Caffeine | |
---|---|---|---|
PRO31 | ☐ | ||
TYR72 | ∗ | ||
ASP74 | △ | ● | |
TRP86 | ☐ | ☐ | ☐ |
GLY120 | △ | ||
GLY121 | △ | △ | △ |
GLY122 | △ ∗ | ||
TYR124 | △ | ||
GLY126 | △ | ||
GLU202 | △ ● | △ | △ |
TRP236 | ☐ | ||
VAL294 | ☐ | ||
PHE295 | ☐ | △ | |
PHE297 | ☐ | ||
TYR337 | ☐ | ☐ | |
PHE338 | ☐ | ☐ | |
TYR341 | ☐ | ☐ | |
TRP439 | △ | ||
HIS447 | ☐ | ☐ | ☐ |
GLY448 | △ | ||
TYR449 | △ |
βb-casomorphin-5 | βb-casomorphin-7 | Caffeine | |
---|---|---|---|
GLN67 | △ | ||
ASN68 | △ | ||
ILE69 | △ | ||
ASP70 | △ | △ | |
TRP82 | ☐ | ☐ ● | ☐ |
PRO84 | △ | ||
THR120 | ☐ | ||
GLU197 | △ ● | ||
SER198 | △ | ||
THR284 | △ | ||
PRO285 | △ | ||
LEU286 | ☐ | ||
ALA328 | ☐ | ☐ | |
PHE329 | ☐ | ||
TYR332 | ☐ | △ ☐ | △ |
TRP430 | |||
MET437 | ☐ | ||
HIS438 | △ | △ ● | ☐ ● |
TYR440 | ☐ |
Ligand | Experimental Ki (μM) | Inhibition (%) at 1000 μg/mL | IC50 (μg/mL) | |||
---|---|---|---|---|---|---|
AChE | BChE | AChE | BChE | AChE | BChE | |
β-casomorphin-5 | 3814.6 | 127.2 | 34% | 67% | 7151 | 238.5 |
β-casomorphin-7 | 1666.4 | 76.3 | 43% | 81% | 4255 | 194.7 |
Caffeine | 11.8 | 1514.0 | 97% | 48% | 7.4 | 949.7 |
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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
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 StyleJi, 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