Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases
Abstract
:1. Introduction
2. Results
2.1. In Silico Physicochemical Characteristics of Nicotinamide Derivatives
2.2. Reversible Inhibition of AChE and BChE by Nicotinamide Derivatives
2.3. Molecular Docking Studies
2.4. Cytotoxicity of Nicotinamide Derivatives
2.5. Effect of Nicotinamide Derivatives on Intracellular Signalling in HEK293 Cells
3. Discussion
4. Materials and Methods
4.1. Nicotinamide Derivatives and Their Physicochemical Characteristics In Silico
4.2. Reagents and Enzymes
4.3. AChE and BChE Reversible Inhibition
4.4. Molecular Docking
4.5. Cytotoxicity Assay
4.6. Analysis of Intracellular Signalling by Western Blot (WB)
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ACC | acetyl-CoA carboxylase |
AChE | acetylcholinesterase |
AD | Alzheimer’s disease |
Akt | protein kinase B |
AMPK | AMP-activated protein kinase |
ATCh | acetylthiocholine |
BChE | butyrylcholinesterase |
DMEM | Dulbecco′s Modified Eagle′s Medium |
DTNB | 5,5′-dithiobis(2-nitrobenzoic acid |
EDTA | ethylenediaminetetraacetic acid |
EMEM | Eagle’s Minimum Essential Medium |
ERK | extracellular signal-regulated kinase |
GAPDH | glyceraldehyde 3-phosphate dehydrogenase |
HBA | hydrogen bond acceptors |
HBD | hydrogen bond donors |
HIF-1α | hypoxia-inducible factor-1α |
IC50 | half maximal inhibitory concentration |
logP | lipophilicity |
M | molecular weight |
mTOR | mammalian target of rapamycin |
NAD | nicotinamide adenine dinucleotide |
PBS | phosphate buffer saline |
RB | number of rotating bonds |
S6RP | S6 ribosomal protein |
TPSA | topological polar surface area |
Appendix A
Appendix A.1. Molecular Docking
Appendix A.2. The Predicted Non-Bonding Interactions for Modelled Complexes by Molecular Docking
Model Complex | Amino Acid | Type of Non-Bonding Interaction |
---|---|---|
6-AChE | Ser203 | Hydrogen bond |
Tyr341 | Hydrogen bond, π-π stacked, π-alkyl | |
Glu202 | Hydrogen bond | |
Tyr124 | Hydrogen bond (x2), π-π T-shaped | |
Trp86 | π-cation (x2), π-π stacked (x2) | |
Tyr337 | Hydrogen bond, π-π stacked | |
Trp286 | π-alkyl | |
8-AChE | Tyr133 | Hydrogen bond (x2) |
Glu202 | Hydrogen bond | |
Gly121 | Hydrogen bond | |
Trp86 | π-cation (x2), π-π stacked (x2) | |
Tyr124 | Hydrogen bond, π-π T-shaped | |
Tyr337 | Hydrogen bond, π-π T-shaped | |
Trp286 | π-π stacked | |
Tyr341 | π-π T-shaped | |
6-BChE | Trp82 | π-cation (x2), π-π stacked (x2), π-π T-shaped |
Tyr332 | Hydrogen bond, π-π stacked, π-alkyl | |
Tyr440 | π-π stacked | |
Ala328 | π-alkyl | |
8-BChE | Ser198 | Hydrogen bond |
His438 | Hydrogen bond (x2) | |
Trp82 | π-cation (x2), π-π stacked (x2), π-π T-shaped (x2) | |
Asp70 | π-anion | |
Ala328 | π-alkyl (x2) |
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Compound | −R | logBB * | Level ** |
---|---|---|---|
1 | 4-H | −0.885 | 3 |
2 | 4-F | −0.821 | 3 |
3 | 4-Cl | −0.679 | 3 |
4 | 4-Br | −0.654 | 3 |
5 | 4-NO2 | −1.595 | 3 |
6 | 4-CH3 | −0.735 | 3 |
7 | 4-OCH3 | −1.031 | 3 |
8 | 4-Ph | −0.416 | 2 |
9 | 2-OCH3 | −1.031 | 3 |
Compound | −R | Ki ± SE (µM) | Ki (AChE)/Ki (BChE) | |
---|---|---|---|---|
AChE | BChE | |||
1 | 4-H | 79 ± 11 | 232 ± 20 | 0.34 |
2 | 4-F | 85 ± 15 | 595 ± 73 | 0.14 |
3 | 4-Cl | 33 ± 5 | 224 ± 23 | 0.15 |
4 | 4-Br | 11 ± 3 | 47 ± 15 | 0.23 |
5 | 4-NO2 | 39 ± 5 | 145 ± 24 | 0.27 |
6 | 4-CH3 | 3 ± 1 | 242 ± 22 | 0.01 |
7 | 4-OCH3 | 19 ± 2 | 216 ± 34 | 0.08 |
8 | 4-Ph | 4 ± 0.2 | 8 ± 1 | 0.50 |
9 | 2-OCH3 | 26 ± 4 | 180 ± 18 | 0.14 |
Ethopropazine 1 | - | 161 | 0.16 | 1010 |
Donepezil 2 | - | 0.0043 | 2.3 | 0.0019 |
Tacrin 3 | - | 0.190 | 0.047 | 4.04 |
Huperizine A 3 | - | 0.082 | 74.4 | 0.0011 |
Compound | −R | IC50 (μM) | |
---|---|---|---|
SH-SY5Y | HEK293 | ||
1 | 4-H | ≥800 | ≤800 1 |
2 | 4-F | ≥800 | ≥800 |
3 | 4-Cl | ≤800 1 | 85 ± 1 |
4 | 4-Br | 501 ± 2 | 83 ± 1 |
5 | 4-NO2 | 214 ± 5 | 417 ± 1 |
6 | 4-CH3 | ≥800 | ≤8001 |
7 | 4-OCH3 | ≥800 | ≥800 |
8 | 4-Ph | 257 ± 1 | 155 ± 1 |
9 | 2-OCH3 | ≥800 | ≥800 |
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Zandona, A.; Lihtar, G.; Maraković, N.; Miš, K.; Bušić, V.; Gašo-Sokač, D.; Pirkmajer, S.; Katalinić, M. Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases. Int. J. Mol. Sci. 2020, 21, 8088. https://doi.org/10.3390/ijms21218088
Zandona A, Lihtar G, Maraković N, Miš K, Bušić V, Gašo-Sokač D, Pirkmajer S, Katalinić M. Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases. International Journal of Molecular Sciences. 2020; 21(21):8088. https://doi.org/10.3390/ijms21218088
Chicago/Turabian StyleZandona, Antonio, Gabriela Lihtar, Nikola Maraković, Katarina Miš, Valentina Bušić, Dajana Gašo-Sokač, Sergej Pirkmajer, and Maja Katalinić. 2020. "Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases" International Journal of Molecular Sciences 21, no. 21: 8088. https://doi.org/10.3390/ijms21218088