Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases
Abstract
:1. Introduction
2. Results
2.1. In Vitro hMAO Inhibition and Enzyme Kinetics
2.2. In Silico Docking Simulation of hMAO
2.3. Cell-Based Functional GPCR Assays
2.4. In Silico Docking Simulation of Dopamine Receptors
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. In Vitro Human MAO Inhibition and Enzyme Kinetics
4.3. Cell-Based Functional GPCR Assay
4.4. Measurement of cAMP Level
4.5. Measurement of Intracellular [Ca2+] Levels
4.6. Homology Modeling
4.7. In Silico Molecular Docking Simulation
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Compounds | Human Monoamine Oxidase A (hMAO-A) | ||
---|---|---|---|
IC50 (μM, Mean ± SD) a | Ki Value b | Inhibition Type c | |
1 | 54.79 ± 0.03 | 26.96 ± 3.98 | Competitive |
2 | 70.16 ± 2.60 | 28.29 ± 2.02 | Competitive |
3 | 114.31 ± 2.30 | 46.93 ± 4.12 | Competitive |
Selegiline d | 12.51 ± 1.11 | NT | NT |
Harmine d, e | 0.006 [26] | NT | NT |
Human Monoamine Oxidase B (hMAO-B) | |||
1 | 18.14 ± 1.06 | 17.01 ± 3.31 | Noncompetitive |
2 | 57.71 ± 2.12 | 52.09 ± 5.56 | Noncompetitive |
3 | 90.59 ± 1.72 | 55.19 ± 7.79 f/186.2 ± 10.26 g | Mixed |
Selegiline d | 0.30 ± 0.01 | NT | NT |
Safinamide d,e | 0.00512 [27] | NT | NT |
Compound | Binding Energy (kcal/mol) a | H-bond Interacting Residues b | Hydrophobic Interacting Residues b | Electrostatic Interacting Residues b |
---|---|---|---|---|
1 | −9.54 | Gly110, Thr336, Ile207, Gly214, Ser209 | Val210 (Pi-Sigma, Pi-Alkyl), Ile325 (Pi-Sigma), Phe208 (Pi-Pi Stacked, Pi-Pi T-Shaped), Ile358 (Alkyl), Leu337 (Alkyl), Ile335 (Alkyl), Met350 (Alkyl), Val93 (Pi-Alkyl), | - |
2 | −6.74 | Met300, Leu298, Asp359, Gly404, Cys398, Trp397, Glu400 | Ala302 (Pi-Alkyl, Alkyl) | - |
3 | −8.62 | Gln296, Ile295, Gly404, Tyr410, Met300, Thr183, Ser184 | Pro299, Ala279, Ala302 (Pi-Alkyl) | Glu188 (Pi-Anion) |
Selegiline | −6.54 | - | Ile335 (Pi-Sigma), Leu337 (Pi-Alkyl), FAD600 (Pi-Alkyl), Tyr407 (Pi-Alkyl), Tyr444 (Pi-Alkyl) | - |
HRM c(Harmine) | −6.46 | FAD600 | Tyr444 (Pi-Sigma), FAD600 (Pi-Sigma, Pi-Pi T-shaped, Pi-Alkyl), Tyr444 (Pi-Pi Stacked), Phe352 (Pi-Pi T-shaped), Tyr407 (Pi-Alkyl), Ile335 (Pi-Alkyl) | - |
Compound | Binding Energy (kcal/mol) a | H-bond Interacting Residues b | Hydrophobic Interacting Residues b | Electrostatic Interacting Residues b |
---|---|---|---|---|
1 | −11.09 | His115, Pro476, Glu483 | Phe103 (Pi-Pi Stacked, Pi-Pi T-shaped, Pi-Alkyl), Val106 (Pi-Alkyl), Ile477 (Pi-Alkyl) | Glu483(Pi-Anion) |
2 | −12.65 | Pro104, Asn116, Glu483, Phe103, Thr478 | Tyr112 (Pi-Sigma), Phe103 (Pi-Pi Stacked), Val106 (Alkyl, Pi-Alkyl), Pro102 (Alkyl, Pi-Alkyl), Tyr112 (Pi-Alkyl), Trp119 (Pi-Alkyl), Pro104 (Pi-Alkyl), Leu164 (Pi-Alkyl) | Glu483(Pi-Anion) |
3 | −10.05 | Thr195, Pro104, Asn116, Thr478, Gly193 | Ile477 (Pi-Sigma), Trp119 (Pi-Pi Stacked), Phe103 (Pi-Pi T-shaped), Thr195 (Amide-Pi Stacked), Gly194 (Amide-Pi Stacked), Arg120 (Alkyl, Pi-Alkyl), Val106 (Pi-Alkyl) | Asp123(Pi-Anion), Glu483(Pi-Anion) |
Selegiline c | −7.06 | Ile198 | Tyr398 (Pi-Pi Stacked), Tyr435 (Pi-Pi Stacked), FAD600 (Pi-Pi T-shaped), Leu171 (Alkyl), Cys172 (Alkyl), Phe188 (Pi-Alkyl) | - |
Safinamide c | −9.86 | Cys172, Ile199, Tyr326, Thr201 | Leu171 (Pi-Sigma, Pi-Alkyl), Tyr398 (Pi-Pi Stacked), Tyr326 (Pi-Pi T-shaped), Ile199 (Pi-Alkyl) | - |
Receptors | 1 | 2 | 3 | Reference Drugs |
---|---|---|---|---|
% Stimulation a (% Inhibition b) | % Stimulation a (% Inhibition b) | % Stimulation a (% Inhibition b) | EC50 c (IC50 d) | |
D1 (h) | 17.2 ± 8.4 (87.65 ± 1.19) | 0.85 ± 0.24 (98.85 ± 1.79) | INTER (67.80 ± 9.05) | 28 (2.8) |
D2L (h) | 7.10 ± 1.47 (101.30 ± 0.16) | NSI (99.15 ± 0.77) | 4.10 ± 1.06 (78.55 ± 3.61) | 12 (28) |
D3 (h) | 119.9 ± 2.44 (−28.7 ± 11.15) | 124.3 ± 0.76 (−27.4 ± 7.79) | 102.8 ± 1.36 (−13.4 ± 1.87) | 4.1 (20) |
D4 (h) | 86.30 ± 0.99 (−20.8 ± 6.93) | 90.45 ± 0.14 (−29.6 ± 7.21) | 46.10 ± 1.76 (26.9 ± 5.09) | 21 (150) |
Target | Compounds | Binding Energy (kcal/mol) | H-bond Interaction Residues | Hydrophobic Interacting Residues | Electrostatic Interacting Residues |
---|---|---|---|---|---|
hD1R | Dopamine a (agonist) | −5.59 | Asp103 (Salt bridge), Ser202, Asn292, Ser199 | Phe289 (Pi-Pi T-shaped), Ile104 (Pi-Alkyl) | Phe288(Pi-Cation) |
SCH23390 a (antagonist) | − 6.94 | Asp103 (Salt bridge), Ser199, Ser202 | Leu190 (Pi-sigma), Phe288 (Pi-Pi T-shaped), Ile104 (Pi-Alkyl), Ala195 (Pi-Alkyl) | - | |
1 | −9.22 | Lys81, Leu291, Asp314, Ser188 | Leu295 (Pi-sigma), Phe313 (Pi-Pi Stacked), Phe306 (Pi-Pi T-shaped), Ser188 (Amide-Pi Stacked), Leu295 (Pi-Alkyl), Leu291 (Pi-Alkyl) | Lys81(Pi-Cation), Asp314(Pi-Anion) | |
2 | −7.1 | Lys81, Ser107, Ser202, Asp187, Asp103, Ser198 | Val100 (Pi-sigma), Val317 (Pi-Sigma, Pi-Alkyl), Phe313 (Pi-Pi T-shaped), Leu190 (Alkyl), Cys186 (Alkyl), Phe288 (Pi-Alkyl), Ile104 (Pi-Alkyl) | Asp187 (Pi-Anion) | |
3 | −9.2 | Asp187, Ser188 | Asp187 (Pi-Sigma). Leu295 (Pi-Sigma, Pi-Alkyl), Phe30 6 (Pi-Pi T-shaped), Pro171 (Pi-Alkyl), Arg192 (Pi-Alkyl), Ala195 (Pi-Alkyl) | - |
Target | Compounds | Binding Energy (kcal/mol) | H-bond Interaction Residues | Hydrophobic Interacting Residues | Electrostatic Interacting Residues |
---|---|---|---|---|---|
hD2LR | Dopamine a (agonist) | −6.98 | Asp114 (Salt bridge), Tyr416, Thr119 | Trp386 (Pi-Pi T-shaped), Val115 (Pi-Alkyl) | - |
Risperidone a (agonist) | −12.7 | Asp114 (salt bridge), Thr119 | Trp100 (Pi-Pi T-shaped, Pi-Alkyl), Trp386 (Pi-Pi T-shaped), Val91(Alkyl), Leu94 (Alkyl), Val115 (Alkyl, Pi-Alkyl), Val111 (Alkyl), Ile184 (Alkyl), Phe110 (Pi-Alkyl), Phe389 (Pi-Alkyl), Cys118 (Pi-Alkyl), Ala122 (Pi-Alkyl) | - | |
Butaclamol a (antagonist) | −6.9 | Asp114 (Salt bridge), Ser193 | Phe389 (Pi-Pi Stacked, Pi-Pi T-shaped, Pi-Alkyl), Tyr416 (Pi-Pi Stacked), Cys118 (Alkyl), Phe198 (Pi-Alkyl), Trp386 (Pi-Alkyl), Phe390 (Pi-Alkyl) | - | |
1 | −8.11 | Ser197, Asp114, Thr412, | Thr412 (Pi-Sigma), Phe110 (Pi-Sigma), Trp110 (Pi-Pi T-shaped, Pi-Alkyl), Trp386 (Pi-Pi T-shaped), Tyr416 (Pi-Pi- T-shaped), Val111 (Alkyl), Ile184 (Alkyl), | Asp114 (Pi-Anion) | |
2 | −8.23 | Asn396, Tyr408, Ile184 | Tyr408 (Pi-Pi Stacked), Tyr100 (Pi-Pi T-shaped), Phe389 (Pi-Alkyl), Tyr416 (Pi-Alkyl), Ile184 (Pi-Alkyl), Val190 (Pi-Alkyl) | - | |
3 | −10.45 | Trp100, Cys118, Ser193, Asp114 | Ile184 (Pi-Sigma, Alkyl), Trp100 (Pi-Pi T-shaped), Trp386 (Pi-Pi T-shaped), Val190 (Alkyl), Phe189 (Pi-Alkyl), Val115 (Pi-Alkyl) | Asp114 (Pi-Anion) |
Target | Compounds | Binding Energy (kcal/mol) | H-bond Interaction Residues | Hydrophobic Interacting Residues | Electrostatic Interacting Residues |
---|---|---|---|---|---|
hD3R | Dopamine a (agonist) | −5.72 | Asp110 (Salt bridge), Tyr373, Val111, Thr115, Ser196 | Val111 (Pi-Alkyl), Cys114 (Pi-Alkyl) | |
Eticlopride a (antagonist) | −9.22 | Asp110 (Salt bridge), Tyr373 | Phe345 (Pi-Pi T-shaped), Ile183 (Alkyl, Pi-Alkyl), Val189 (Alkyl), VAl111 (Pi-Alkyl) | ||
(+)-butaclamol a (antagonist) | −10.69 | Asp110(Salt bridge) | Val111 (Alkyl), Cys114 (Alkyl), Trp342 (Pi-Alkyl), Phe345 (Pi-Alkyl), Phe346 (Pi-Alkyl), Val86 (Pi-Alkyl) | ||
1 | −5.89 | Tyr365, Cys181, Ser366, Thr369 | Ile183 (Pi-Sigma), Phe345 (Pi-Pi T-shaped), His349 (Pi-Pi T-shaped), Tyr365 (Pi-Pi T-shaped), Val86 (Alkyl, Pi-Alkyl), Leu89 (Alkyl), Phe106 (PI-Alkyl), Val107 (Pi-Alkyl), Val111 (Pi-Alkyl) | Asp110 (Pi-Anion) | |
2 | −7.45 | Tyr365, Thr369, Cys181, | Thr369 (Pi-Sigma), Phe345(Pi-Pi Stacked, Pi-Alkyl), Phe106 (Pi-Pi T-shaped), Tyr365 (Pi-Pi T-shaped), Val86 (Alkyl), Leu89 (Alkyl), Phe346 (Pi-Alkyl), Val107 (PI-Alkyl) | Asp110 (Pi-Anion), | |
3 | −10.41 | Ile183, Val110, Thr115 | Leu89 (Pi-Sigma), Thr359 (Pi-Sigma), Phe345 (Pi-Pi Stacked), Tyr365 (PI-Pi T-shaped), Val86 (Alkyl, Pi-Alkyl), Tyr36 (Pi-Alkyl), Val111 (Pi-Alkyl), Cys114 (Pi-Alkyl), | Asp110 (Pi-Anion) |
Target | Compounds | Binding Energy (kcal/mol) | H-bond Interaction Residues | Hydrophobic Interacting Residues | Electrostatic Interacting Residues |
---|---|---|---|---|---|
hD4R | Dopamine a (agonist) | −6.1 | Asp115(Salt bridge), Thr120, Ser196, Tyr438 | Cys119(Pi-Alkyl), Val116(Pi-Alkyl), Phe411(Pi-Pi T-shaped) | |
Nemonapride a (agonist) | −13.08 | Asp115(Salt bridge), Tyr438, Ser196 | Val116 (Pi-Sigma), Phe91 (Pi-Pi T-shaped), Phe410 (Pi-Pi T-shaped), Leu90 (Amide-Pi Stacked), Val193 (Alkyl), Leu111 (Pi-Alkyl) | ||
Clozapine a (antagonist) | −10.14 | Asp115(Salt bridge) | Leu187(Pi-Sigma), Phe410(Pi-PI T-shaped), His414(Pi-Pi T-shaped), Val116(Alkyl, Pi-Alkyl), Val193(Pi-Alkyl) | ||
1 | −9.67 | Ser196, Leu187, Val430, Thr434 | Val116 (Pi-Sigma, Pi-Alkyl), Leu187 (Pi-Sigma), Thr434 (Pi-Sigma), Phe411 (Pi-Pi T-shaped), His414 (PI-Pi T-shaped), Phe410 (Pi-Pi T-shaped), Met112 (Alkyl), Cys185 (Alkyl), Cys119 (Alkyl, Pi-Alkyl), Arg186 (Pi-Alkyl) | Asp115 (Pi-Anion) | |
2 | −10.34 | Ser197, Thr434, Asp115, Tyr438 | Val193 (Pi-sigma), His414 (Pi-Pi Stacked, Pi-Pi T-shaped), Met112 (Alkyl), Leu187 (Alkyl, Pi-Alkyl), Phe91 (Pi-Alkyl), Arg186 (Pi-Alkyl),Val116 (Pi-Alkyl) | Asp115 (Pi-Anion) | |
3 | −12.42 | Leu187, Asp115, Ser196 | Leu187 (Pi-Sigma, Alkyl, Pi-Alkyl), Phe410 (Pi-Pi T-shaped), His414 (Pi-Pi T-shaped, Pi-Alkyl), Val193 (Alkyl, Pi-Alkyl), Val116 (Pi-Alkyl) | Asp115 (Pi-Anion) |
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Paudel, P.; Park, S.E.; Seong, S.H.; Jung, H.A.; Choi, J.S. Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases. Int. J. Mol. Sci. 2019, 20, 6232. https://doi.org/10.3390/ijms20246232
Paudel P, Park SE, Seong SH, Jung HA, Choi JS. Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases. International Journal of Molecular Sciences. 2019; 20(24):6232. https://doi.org/10.3390/ijms20246232
Chicago/Turabian StylePaudel, Pradeep, Se Eun Park, Su Hui Seong, Hyun Ah Jung, and Jae Sue Choi. 2019. "Novel Diels–Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases" International Journal of Molecular Sciences 20, no. 24: 6232. https://doi.org/10.3390/ijms20246232