Determination of Potential Lead Compound from Magnolia officinalis for Alzheimer’s Disease through Pharmacokinetic Prediction, Molecular Docking, Dynamic Simulation, and Experimental Validation
Abstract
:1. Introduction
2. Results
2.1. Drug-Like Properties of the Compounds in M. officinalis
2.2. Pharmacokinetic Properties of Compounds in M. officinalis
2.3. Molecular Docking on Enzymatic Targets: hBACE1, hAChE, hQC, and hGSK-3ß
2.4. Binding Interaction of the Best Compound with Multi-Enzyme Targets
2.5. MD Simulations of Honokiol with hBACE1, hAChE, hQC, and hGSK-3ß
2.6. Inhibitory Effects of Honokiol on hBACE1, AChE, hQC, and hGSK-3β
2.7. Kinetic Studies of hBACE1, AChE, hQC, and hGSK-3β Inhibition by Honokiol
3. Discussion
4. Materials and Methods
4.1. Collection of M. officinalis Compounds
4.2. Drug-Likeness and ADMET Analysis
4.3. Molecular Docking Simulation
4.4. MD Simulation
4.5. Reagents
4.6. hBACE1 Inhibitory Activity
4.7. AChE Inhibitory Activity
4.8. hQC Inhibitory Activity
4.9. hGSK-3β Activity
4.10. Enzymatic Kinetics on hBACE1, hAChE, hQC, and hGSK-3β
4.11. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Compound | Drug-Likeness Property | Pharmacokinetic Profiles | ||
---|---|---|---|---|
Lipinski’s Rule | Veber’s Rule | BBB Penetration | P-gp Substrate | |
(+)-Syringaresinol (1) | Yes | Yes | No | Yes |
Khusilol (2) | Yes | Yes | Yes | No |
Asimilobine (3) | Yes | Yes | Yes | Yes |
Magnoflorine (4) | Yes | Yes | Yes | Yes |
Tembetarine (5) | Yes | Yes | Yes | Yes |
Ferulic acid methyl ester (6) | Yes | Yes | Yes | No |
3-Pinanone (9) | Yes | Yes | Yes | No |
6,6-Dimethyl-2-methylene-bicyclo[2.2.1]-heptan-3-one (11) | Yes | Yes | Yes | Yes |
Xanthoplanine (13) | Yes | Yes | Yes | Yes |
N-Methylbulbocapnine (14) | Yes | Yes | Yes | Yes |
N-Methylcoclaurine (15) | Yes | Yes | Yes | Yes |
N-Nornuciferine (16) | Yes | Yes | Yes | Yes |
Anonaine (18) | Yes | Yes | Yes | Yes |
Borneol (19) | Yes | Yes | Yes | No |
Borneol acetate (20) | Yes | Yes | Yes | No |
Caffeic acid methyl ester (21) | Yes | Yes | Yes | No |
Camphor (23) | Yes | Yes | Yes | No |
Caryophyllene oxide (25) | Yes | Yes | Yes | No |
cis-Linalool oxide (26) | Yes | Yes | Yes | No |
Corytuberine (28) | Yes | Yes | Yes | Yes |
Dienestrol (29) | Yes | Yes | Yes | No |
Esculetin (32) | Yes | Yes | No | No |
Gallic acid (34) | Yes | Yes | No | No |
Glaucine (36) | Yes | Yes | Yes | Yes |
Hexanal (38) | Yes | Yes | Yes | No |
Honokiol (39) | Yes | Yes | Yes | No |
Isomagnolol (42) | Yes | Yes | Yes | No |
Limonene (43) | Yes | Yes | Yes | No |
Lirinidine (44) | Yes | Yes | Yes | Yes |
Liriodenine (45) | Yes | Yes | Yes | Yes |
Lotusine (46) | Yes | Yes | Yes | Yes |
Magnaldehyde D (47) | Yes | Yes | Yes | No |
Magnocurarine (48) | Yes | Yes | Yes | Yes |
Magnolignan A (49) | Yes | Yes | No | No |
Magnolignan C (50) | Yes | Yes | No | No |
Magnolol (51) | Yes | Yes | Yes | No |
Michelalbine (56) | Yes | Yes | Yes | Yes |
Nandigerine (58) | Yes | Yes | Yes | Yes |
Nornuciferine (61) | Yes | Yes | Yes | Yes |
Obovatol (62) | Yes | Yes | Yes | No |
Palmidin B (65) | Yes | Yes | No | No |
Phenol (67) | Yes | Yes | Yes | No |
Puterine (69) | Yes | Yes | Yes | Yes |
Randaiol (70) | Yes | Yes | Yes | No |
Reticuline (71) | Yes | Yes | Yes | Yes |
Roemerine (72) | Yes | Yes | Yes | Yes |
Syringin (73) | Yes | Yes | No | No |
Xanthoplanine (74) | Yes | Yes | Yes | Yes |
α-Eudesmol (76) | Yes | Yes | Yes | No |
α-Terpineol (78) | Yes | Yes | Yes | No |
β-Eudesmol (79) | Yes | Yes | Yes | No |
γ-Eudesmol (80) | Yes | Yes | Yes | No |
γ-Gurjunene epoxide (81) | Yes | Yes | Yes | No |
Ligand | AMES Toxicity | Maximum Tolerated Dose in Human | Oral Rat Acute Toxicity (LD50, mol/kg) | Oral Rat Chronic Toxicity (log mg/kg) |
---|---|---|---|---|
Khusilol (2) | No | −0.279 | 1.673 | 1.335 |
Ferulic acid methyl ester (6) | No | 0.309 | 1.653 | 1.908 |
3-Pinanone (9) | No | 0.374 | 1.692 | 1.932 |
Borneol (19) | No | 0.577 | 1.707 | 1.877 |
Borneol acetate (20) | No | 0.526 | 1.904 | 1.875 |
Caffeic acid methyl ester (21) | No | −0.154 | 2.023 | 1.594 |
Camphor (23) | No | 0.473 | 1.653 | 1.981 |
Caryophyllene oxide (25) | No | 0.148 | 1.548 | 1.224 |
cis-Linalool oxide (26) | No | 0.891 | 1.917 | 2.221 |
Dienestrol (29) | No | 0.191 | 2.324 | 1.840 |
Hexanal (38) | No | 0.833 | 1.762 | 1.922 |
Honokiol (39) | No | 0.305 | 2.184 | 1.791 |
Isomagnolol (42) | Yes | 0.724 | 2.025 | 1.929 |
Limonene (43) | No | 0.777 | 1.880 | 2.336 |
Magnaldehyde D (47) | No | 0.462 | 1.827 | 1.772 |
Magnolol (51) | No | 0.468 | 1.976 | 1.851 |
Obovatol (62) | No | 0.497 | 1.776 | 1.586 |
Phenol (67) | No | 0.540 | 2.153 | 2.011 |
Randaiol (70) | No | 0.391 | 2.383 | 1.457 |
α-Eudesmol (76) | No | 0.131 | 1.680 | 1.231 |
α-Terpineol (78) | No | 0.886 | 1.923 | 1.945 |
β-Eudesmol (79) | No | −0.220 | 1.727 | 1.304 |
γ-Eudesmol (80) | No | 0.055 | 1.681 | 1.249 |
γ-Gurjunene epoxide (81) | No | 0.347 | 1.647 | 1.428 |
Ligand | CID No. | Binding Energy (kcal/mol) | |||
---|---|---|---|---|---|
hBACE1 (6JSE) | hAChE (4EY7) | hQC (3PBB) | hGS3-β (1Q5K) | ||
Khusilol (2) | 556427 | −6.939 | −8.324 | −8.288 | −7.686 |
Ferulic acid methyl ester (6) | 5357283 | −6.146 | −7.533 | −6.973 | −6.403 |
3-Pinanone (9) | 11038 | −5.956 | −7.226 | −5.301 | −5.509 |
Borneol (19) | 1201518 | −5.303 | −6.524 | −4.472 | −5.129 |
Borneol acetate (20) | 93009 | −5.862 | −7.834 | −5.122 | −5.788 |
Caffeic acid methyl ester (21) | 689075 | −6.129 | −7.489 | −7.261 | −6.393 |
Camphor (23) | 2537 | −5.220 | −6.983 | −4.877 | −5.014 |
Caryophyllene oxide (25) | 1742210 | −7.275 | −8.564 | −5.876 | −6.721 |
cis-Linalool oxide (26) | 6428573 | −5.685 | −6.551 | −5.801 | −5.434 |
Dienestrol (29) | 667476 | −7.371 | −9.494 | −7.730 | −8.395 |
Hexanal (38) | 6184 | −3.791 | −4.576 | −4.641 | −3.992 |
Honokiol (39) | 72303 | −7.784 | −9.442 | −8.403 | −8.303 |
Limonene (43) | 22311 | −5.887 | −7.000 | −6.650 | −6.386 |
Magnaldehyde D (47) | 5319189 | −7.531 | −9.390 | −7.660 | −7.079 |
Magnolol (51) | 72300 | −7.836 | −9.825 | −7.875 | −7.284 |
Obovatol (62) | 100771 | −7.418 | −9.827 | −7.685 | −7.675 |
Phenol (67) | 996 | −4.415 | −5.250 | −5.684 | −4.501 |
Randaiol (70) | 13337243 | −7.733 | −8.558 | −7.251 | −7.382 |
α-Eudesmol (76) | 92762 | −7.719 | −9.856 | −7.222 | −7.884 |
α-Terpineol (78) | 17100 | −5.818 | −7.086 | −6.530 | −6.173 |
β-Eudesmol (79) | 91457 | −7.829 | −8.482 | −7.496 | −7.739 |
γ-Eudesmol (80) | 6432005 | −7.692 | −9.668 | −8.062 | −7.473 |
γ-Gurjunene epoxide (81) | 91750423 | −6.940 | −7.956 | −6.669 | −6.362 |
C6R 1 | 138857908 | −10.400 | - | - | - |
E20 1 | 1150567 | - | −12.200 | - | - |
PDB 1 | 6539196 | - | - | −6.300 | -- |
TMU 1 | 68670561 | - | - | −8.000 |
Compound | Target Marker | IC50 1 | Ki 2 | Inhibition Mode 3 |
---|---|---|---|---|
Honokiol | hBACE1 4 | 20.64 ± 0.80 µM | 27.3 µM | Non-competitive |
AChE 4 | 78.85 ± 1.23 µM | 58.2 µM | Non-competitive | |
hQC 4 | 90.74 ± 1.07 µM | 49.4 µM | Competitive | |
hGSK-3β 4 | 6.70 ± 0.03 µM | 9.8 µM | Non-competitive |
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Youn, K.; Jun, M. Determination of Potential Lead Compound from Magnolia officinalis for Alzheimer’s Disease through Pharmacokinetic Prediction, Molecular Docking, Dynamic Simulation, and Experimental Validation. Int. J. Mol. Sci. 2024, 25, 10507. https://doi.org/10.3390/ijms251910507
Youn K, Jun M. Determination of Potential Lead Compound from Magnolia officinalis for Alzheimer’s Disease through Pharmacokinetic Prediction, Molecular Docking, Dynamic Simulation, and Experimental Validation. International Journal of Molecular Sciences. 2024; 25(19):10507. https://doi.org/10.3390/ijms251910507
Chicago/Turabian StyleYoun, Kumju, and Mira Jun. 2024. "Determination of Potential Lead Compound from Magnolia officinalis for Alzheimer’s Disease through Pharmacokinetic Prediction, Molecular Docking, Dynamic Simulation, and Experimental Validation" International Journal of Molecular Sciences 25, no. 19: 10507. https://doi.org/10.3390/ijms251910507