Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates
Abstract
:1. Introduction
2. Results and Discussion
2.1. Development of New Model for Prediction of Drug–Target Networks
2.1.1. Model Training and Validation
Descriptor | Sub-Set | Stat. a | % | Groups | Ci(mj)pred = 1 | Ci(mj)pred = 0 | Reference |
---|---|---|---|---|---|---|---|
MI-Entropy | Train | Sp | 79.0 | Lij(Cq)obs = 1 | 1092 | 290 | This work |
Sn | 91.5 | Lij(Cq)obs = 0 | 412 | 4438 | |||
Ac | 88.7 | Total | |||||
CV | Sp | 81.3 | Lij(Cq)obs = 1 | 379 | 87 | ||
Sn | 92.6 | Lij(Cq)obs = 0 | 119 | 1492 | |||
Ac | 90.1 | Total | |||||
MI spectral moments | Train | Sp | 84.6 | Lij(Cq)obs = 1 | 1172 | 214 | [52] |
Sn | 82.4 | Lij(Cq)obs = 0 | 224 | 1051 | |||
Ac | 83.5 | Total | |||||
CV | Sp | 83.3 | Lij(Cq)obs = 1 | 385 | 77 | ||
Sn | 81.6 | Lij(Cq)obs = 0 | 78 | 347 | |||
Ac | 82.5 | Total | |||||
TM spectral moments | Train | Sp | 81.3 | Lij(Cq)obs = 1 | 1533 | 352 | [51] |
Sn | 98.0 | Lij(Cq)obs = 0 | 36 | 1762 | |||
Ac | 89.5 | Total | |||||
CV | Sp | 81.0 | Lij(Cq)obs = 1 | 513 | 120 | ||
Sn | 97.7 | Lij(Cq)obs = 0 | 14 | 585 | |||
Ac | 89.1 | Total |
Compound (i) | pij(cq) | Assay ID | Measure (Units) | Organism | Target Protein |
---|---|---|---|---|---|
Arecoline | 0.94 | 796814 | Efficiency (%) | rno | Muscarinic acetylcholine receptor |
Bipinnatin-A | 1.00 | 751272 | Inhibition (%) | mmu | Acetylcholine receptor protein β chain |
Carachol | 0.99 | 796814 | Efficiency (%) | rno | Muscarinic acetylcholine receptor |
Caulophylline | 0.96 | 838016 | EC50 (nM) | hsa | Neuronal acetylcholine receptor; α4/β2 |
Citalopram | 0.99 | 740208 | Ki (nM) | mmu | Dopamine transporter |
Condelphine | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
Delcorine | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
Delsoline | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
Desipramine | 0.99 | 797692 | −Log(IC50) (nM) | rno | Norepinephrine transporter |
Elatine | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
Emopamil | 1.00 | 817225 | −Log(IC50) (nM) | rno | Voltage-gated R-type calcium channel α-1E subunit |
Epibatidine | 0.94 | 838016 | EC50 (nM) | hsa | Neuronal acetylcholine receptor; α4/β2 |
Epibatidine | 0.19 | 825420 | Efficacy (%) | hsa | Neuronal acetylcholine receptor; α4/β2 |
Femoxetine | 0.99 | 740206 | Ki (nM) | mmu | Dopamine transporter |
Femoxetine | 0.99 | 740207 | Ki (nM) | mmu | Norepinephrine transporter |
Femoxetine | 0.99 | 740208 | Ki (nM) | mmu | Dopamine transporter |
Fisetin | 0.05 | 1027709 | %max (%) | mmu | HT22 cells |
Fluoxetine | 0.99 | 740207 | Ki (nM) | mmu | Norepinephrine transporter |
Fluoxetine | 0.99 | 740208 | Ki (nM) | mmu | Dopamine transporter |
Imipramine | 0.99 | 740206 | Ki (nM) | mmu | Dopamine transporter |
Imipramine | 0.99 | 740207 | Ki (nM) | mmu | Norepinephrine transporter |
Imipramine | 0.99 | 740208 | Ki (nM) | mmu | Dopamine transporter |
Inuline | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
Karacoline | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
l-Arginine | 0.99 | 755144 | Activity (nM) | hsa | Nitric-oxide synthase, brain |
l-NIL | 0.59 | 752266 | −Log(IC50) (nM) | hsa | Nitric-oxide synthase, brain |
l-NMMA | 0.99 | 876477 | −Log(IC50) (nM) | hsa | Nitric-oxide synthase, brain |
l-NNA | 0.98 | 752385 | −Log(IC50) (nM) | hsa | Nitric-oxide synthase, brain |
l-NNA | 0.86 | 752276 | Ki (nM) | hsa | Nitric-oxide synthase, brain |
LY-379268 | 0.99 | 714803 | Activity (nM) | hsa | Metabotropic glutamate receptor 4 |
LY-379268 | 0.99 | 877752 | Activity (nM) | hsa | Metabotropic glutamate receptor 2 |
LY-379268 | 0.99 | 718128 | Activity (nM) | hsa | Metabotropic glutamate receptor 6 |
LY-389795 | 0.99 | 718128 | Activity (nM) | hsa | Metabotropic glutamate receptor 6 |
LY-389795 | 0.98 | 715721 | Activity (nM) | hsa | Metabotropic glutamate receptor 5 |
LY-389795 | 0.97 | 714446 | Activity (nM) | hsa | Metabotropic glutamate receptor 3 |
Lycoctonine | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
M826 | 1.00 | 841780 | Ki (nM) | hsa | Caspase-3 |
M827 | 1.00 | 841780 | Ki (nM) | hsa | Caspase-3 |
Methyllycaconitine | 1.00 | 750084 | Ki (nM) | rno | Neuronal acetylcholine receptor protein α-10 subunit |
NBQX | 0.99 | 641893 | −Log(IC50) (nM) | rno | Glutamate receptor ionotropic, AMPA 2 |
NBQX | 0.99 | 641893 | −Log(IC50) (nM) | rno | Glutamate receptor ionotropic, AMPA 4 |
NBQX | 0.99 | 641893 | −Log(IC50) (nM) | rno | Glutamate receptor ionotropic, AMPA 3 |
NBQX | 0.99 | 641893 | −Log(IC50) (nM) | mmu | Glutamate receptor ionotropic, AMPA 1 |
Nipecotic acid | 0.28 | 785010 | −Log(IC50) (nM) | rno | GABA transporter 1 |
Nipecotic acid | 0.28 | 785010 | −Log(IC50) (nM) | rno | GABA transporter 2 |
Nipecotic acid | 0.28 | 785010 | −Log(IC50) (nM) | rno | GABA transporter 3 |
Nipecotic acid | 0.28 | 785010 | −Log(IC50) (nM) | rno | Betaine transporter |
NOHA | 0.04 | 755137 | NO formation (%) | rno | Nitric-oxide synthase, brain |
Norepinephrine | 0.98 | 780755 | Concentration (% dose·g−1) | rno | |
Nudicauline | 1.00 | 748943 | −Log(IC50) (nM) | rno | Neuronal acetylcholine receptor protein α-7 subunit |
Omega nitro-arginine | 0.99 | 752258 | Ki (nM) | hsa | Nitric-oxide synthase, brain |
Oxotremorine | 0.84 | 798083 | pD2 | rno | Muscarinic acetylcholine receptor M1 |
Paroxetine | 1.00 | 740206 | Ki (nM) | mmu | Dopamine transporter |
RedAm-Ethyl | 0.33 | 840782 | Selectivity | hsa | Nitric-oxide synthase, endothelial |
RedAm-Ethyl | 0.28 | 840782 | Selectivity | hsa | Nitric-oxide synthase, brain |
Resveratrol | 0.99 | 1613870 | EC50 (nM) | hsa | Nuclear factor NF-κB p105 subunit |
Resveratrol | 0.99 | 1613870 | EC50 (nM) | hsa | Nuclear factor NF-κB p65 subunit |
Stemofoline | 1.00 | 936299 | EC50 (nM) | hvi | Nicotinic acetylcholine receptor α1 subunit |
Thiocytisine | 0.51 | 857972 | Log Ki | rno | Neuronal acetylcholine receptor; α4/β2 |
2.1.2. Comparison with Other ALMA Models
Statistics | p1(cj)·<θk(cq)> | Experimental Measure (units) | Statistics | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
n(sx) | n1(sx) | p1(sx) | 1 | 2 | 3 | 4 | 5 | n(sx) | n1(sx) | p1(sx) | 1 | 2 | 3 | 4 | |
2438 | 2148 | 0.88 | 2.03 | 2.08 | 2.04 | 2.04 | 2.03 | ED50 (μg·kg−1) | 19 | 14 | 0.74 | 1.58 | 1.6 | 1.59 | 1.59 |
2149 | 1975 | 0.92 | 1.87 | 1.91 | 1.89 | 1.89 | 1.88 | ED50 (nM) | 18 | 14 | 0.78 | 2.14 | 2.17 | 2.14 | 2.14 |
1501 | 1418 | 0.94 | 2.01 | 2.06 | 2.03 | 2.02 | 2.01 | NO formation (%) | 18 | 6 | 0.33 | 0.63 | 0.64 | 0.63 | 0.63 |
486 | 102 | 0.21 | 0.5 | 0.51 | 0.51 | 0.51 | 0.51 | Efficiency (%) | 14 | 11 | 0.79 | 1.58 | 1.61 | 1.6 | 1.6 |
299 | 130 | 0.43 | 0.89 | 0.91 | 0.89 | 0.89 | 0.88 | Kup (mL·min−1·g−1) | 13 | 5 | 0.38 | 0.75 | 0.76 | 0.76 | 0.76 |
222 | 105 | 0.47 | 1.22 | 1.24 | 1.23 | 1.23 | 1.22 | Conc. (%·dose·g−1) | 12 | 7 | 0.58 | 1.14 | 1.15 | 1.14 | 1.14 |
193 | 93 | 0.48 | 0.99 | 1 | 0.99 | 0.99 | 0.98 | Efficacy (%) | 12 | 6 | 0.5 | 0.58 | 0.58 | 0.58 | 0.59 |
166 | 61 | 0.37 | 0.94 | 0.95 | 0.93 | 0.93 | 0.92 | Ratio Ki | 12 | 2 | 0.17 | 0.38 | 0.39 | 0.39 | 0.39 |
124 | 72 | 0.58 | 0.96 | 0.97 | 0.96 | 0.96 | 0.96 | MTT reduction (%) | 11 | 4 | 0.36 | 0.58 | 0.57 | 0.57 | 0.56 |
108 | 31 | 0.29 | 0.66 | 0.67 | 0.66 | 0.66 | 0.65 | Relative potency | 11 | 4 | 0.36 | 0.93 | 0.94 | 0.92 | 0.92 |
98 | 93 | 0.95 | 1.74 | 1.77 | 1.75 | 1.75 | 1.74 | ED50 (μg·mL−1) | 10 | 4 | 0.4 | 0.99 | 1.02 | 0.99 | 0.99 |
84 | 26 | 0.31 | 0.51 | 0.51 | 0.51 | 0.52 | 0.52 | Activity | 8 | 5 | 0.63 | 1.98 | 2.01 | 1.99 | 1.99 |
56 | 17 | 0.3 | 0.56 | 0.58 | 0.57 | 0.57 | 0.57 | Damage score | 8 | 2 | 0.25 | 0.5 | 0.51 | 0.5 | 0.49 |
56 | 32 | 0.57 | 1.1 | 1.12 | 1.11 | 1.1 | 1.1 | Mean response | 8 | 5 | 0.63 | 1.44 | 1.48 | 1.46 | 1.46 |
36 | 25 | 0.69 | 1.69 | 1.73 | 1.7 | 1.69 | 1.68 | Survived (%) | 8 | 5 | 0.63 | 1.04 | 1.04 | 1.04 | 1.04 |
20 | 4 | 0.2 | 0.55 | 0.56 | 0.55 | 0.55 | 0.54 | Rescued neurons (%) | 5 | 2 | 0.4 | 0.59 | 0.6 | 0.61 | 0.62 |
n(oj) | n1(oj) | p1(oj) | 1 | 2 | 3 | 4 | 5 | Organism | n(oj) | n1(oj) | p1(oj) | 1 | 2 | 3 | 4 |
2852 | 1998 | 0.7 | 1.51 | 1.54 | 1.52 | 1.52 | 1.51 | B. taurus | 77 | 21 | 0.27 | 0.63 | 0.63 | 0.63 | 0.63 |
4854 | 4090 | 0.84 | 1.82 | 1.86 | 1.83 | 1.83 | 1.82 | C. porcellus | 20 | 16 | 0.8 | 1.35 | 1.36 | 1.35 | 1.35 |
10 | 7 | 0.7 | 1.66 | 1.7 | 1.68 | 1.67 | 1.66 | H. virescens | 5 | 5 | 1 | 2.78 | 2.83 | 2.78 | 2.78 |
241 | 173 | 0.72 | 1.5 | 1.53 | 1.51 | 1.51 | 1.51 | M. domestica | 15 | 15 | 1 | 1.62 | 1.66 | 1.67 | 1.68 |
19 | 11 | 0.58 | 1.34 | 1.37 | 1.35 | 1.35 | 1.34 | C. elegans | 2 | 1 | 0.5 | 1.28 | 1.31 | 1.28 | 1.27 |
8 | 2 | 0.25 | 0.5 | 0.51 | 0.5 | 0.49 | 0.49 | D. melanogaster | 2 | 1 | 0.5 | 1.28 | 1.31 | 1.28 | 1.27 |
n(tj) | n1(tj) | p1(tj) | 1 | 2 | 3 | 4 | 5 | ||||||||
403 | 254 | 0.63 | 1.34 | 1.36 | 1.34 | 1.34 | 1.34 | ||||||||
77 | 21 | 0.27 | 0.63 | 0.63 | 0.63 | 0.63 | 0.63 | ||||||||
128 | 32 | 0.25 | 0.53 | 0.54 | 0.53 | 0.53 | 0.53 | ||||||||
859 | 562 | 0.65 | 1.30 | 1.32 | 1.30 | 1.30 | 1.30 | ||||||||
88 | 18 | 0.20 | 0.50 | 0.51 | 0.50 | 0.50 | 0.50 | ||||||||
1000 | 923 | 0.92 | 1.88 | 1.91 | 1.89 | 1.89 | 1.88 | ||||||||
104 | 90 | 0.87 | 1.82 | 1.87 | 1.84 | 1.84 | 1.82 | ||||||||
79 | 66 | 0.84 | 1.78 | 1.83 | 1.80 | 1.80 | 1.79 | ||||||||
37 | 31 | 0.84 | 1.97 | 2.04 | 2.01 | 2.01 | 2.00 | ||||||||
29 | 28 | 0.97 | 1.98 | 2.02 | 2.00 | 1.99 | 1.98 | ||||||||
n(cj) | n1(cj) | p1(cj)j | 1 | 2 | 3 | 4 | 5 | ||||||||
2000 | 1846 | 0.92 | 1.88 | 1.91 | 1.89 | 1.89 | 1.88 | ||||||||
646 | 646 | 1.00 | 2.31 | 2.37 | 2.32 | 2.30 | 2.28 | ||||||||
390 | 390 | 1.00 | 2.12 | 2.16 | 2.13 | 2.12 | 2.11 | ||||||||
299 | 130 | 0.43 | 0.89 | 0.91 | 0.89 | 0.89 | 0.88 | ||||||||
114 | 99 | 0.87 | 1.46 | 1.48 | 1.46 | 1.46 | 1.45 | ||||||||
74 | 17 | 0.22 | 0.56 | 0.57 | 0.56 | 0.56 | 0.56 | ||||||||
50 | 50 | 1.00 | 2.93 | 2.97 | 2.93 | 2.91 | 2.89 | ||||||||
50 | 50 | 1.00 | 2.93 | 2.97 | 2.93 | 2.91 | 2.89 | ||||||||
50 | 50 | 1.00 | 2.93 | 2.97 | 2.93 | 2.91 | 2.89 | ||||||||
11 | 11 | 1.00 | 2.95 | 3.00 | 2.96 | 2.94 | 2.92 |
2.1.3. Construction of Drug–Target Networks with ALMA Models
Network | Node Type | n | Sh1 a | δ | δin | δout |
---|---|---|---|---|---|---|
Observed | Total | 2450 | 0.00428 | 7 | 3 | 3 |
Compounds | 2103 | 0.00413 | 6 | 3 | 3 | |
Assays | 211 | 0.00575 | 6 | 3 | 3 | |
Rat proteins | 54 | 0.00291 | 7 | 4 | 3 | |
Human proteins | 70 | 0.00568 | 21 | 18 | 3 | |
1 | Total | 2508 | 0.00438 | 7 | 3 | 3 |
Compounds | 2208 | 0.00446 | 6 | 3 | 3 | |
Assays | 183 | 0.00468 | 15 | 11 | 4 | |
Rat proteins | 40 | 0.00279 | 6 | 3 | 3 | |
Human proteins | 67 | 0.00210 | 5 | 1 | 3 | |
2 | Total | 2511 | 0.00428 | 7 | 3 | 3 |
Compounds | 2209 | 0.00445 | 6 | 3 | 3 | |
Assays | 184 | 0.00464 | 15 | 11 | 4 | |
Rat proteins | 40 | 0.00266 | 6 | 3 | 3 | |
Human proteins | 68 | 0.00209 | 4 | 1 | 3 | |
3 | Total | 2511 | 0.0044 | 7 | 3 | 3 |
Compounds | 2209 | 0.00445 | 6 | 3 | 3 | |
Assays | 184 | 0.00464 | 15 | 11 | 4 | |
Rat proteins | 40 | 0.00266 | 6 | 3 | 3 | |
Human proteins | 68 | 0.00209 | 4 | 1 | 3 | |
4 | Total | 2491 | 0.0046 | 7 | 3 | 3 |
Compounds | 2209 | 0.00471 | 6 | 3 | 3 | |
Assays | 184 | 0.00449 | 14 | 11 | 4 | |
Rat proteins | 40 | 0.00251 | 6 | 2 | 3 | |
Human proteins | 68 | 0.00209 | 4 | 1 | 3 | |
5 | Total | 2491 | 0.0046 | 7 | 3 | 3 |
Compounds | 2209 | 0.00471 | 6 | 3 | 3 | |
Assays | 184 | 0.00449 | 14 | 11 | 4 | |
Rat proteins | 40 | 0.00251 | 6 | 2 | 3 | |
Human proteins | 68 | 0.00209 | 4 | 1 | 3 |
2.2. Experimental and Theoretical Study of New Compounds
2.2.1. Synthesis and Experimental Assay of New 1,2-Rasagiline Derivatives
Compound | Formula | % Neuro-Protection | |||||
---|---|---|---|---|---|---|---|
% ANA a | e.s.m. | Glutamate b | e.s.m. | H2O2c | e.s.m. | ||
2 | 0.0 | 2.8 | 0.0 | 6.5 | −2.8 | 1.2 | |
3 | 4.7 | 6.0 | −0.2 | 1.6 | −12.3 | 2.1 | |
4 | 4.2 | 6.5 | −8.1 | 4.9 | −14.2 | 2.1 | |
5 | 1.2 | 5.0 | 3.8 | 5.0 | 2.9 | 1.0 | |
6 | 11.5 | 8.8 | −4.0 | 5.5 | −9.1 | 2.4 | |
7 | 4.0 | 4.5 | 2.6 | 3.9 | -6.1 | 1.1 | |
8 | −1.7 | 6.9 | −5.2 | 5.9 | −8.9 | 1.9 | |
9 | 8.4 | 10.7 | −5.2 | 2.3 | −14.0 | 2.0 |
2.2.2. Using ALMA-Entropy Model to Predicting New Drugs in Other Assays
Si(cj) | Meassure | Assay ID | Target ID | Target a | Neurotoxic Agent |
---|---|---|---|---|---|
2.097 | pA2 | 617971 | 1899 | 5HT3aR | ANA |
2.097 | pA2 | 617969 | 1899 | 5HT3aR | ANA |
2.097 | pA2 | 617971 | 3895 | 5HT3bR | ANA |
2.097 | pA2 | 617969 | 3895 | 5HT3bR | ANA |
1.78 | Selectivity | 848737 | 3568 | bNOS | H2O2 |
1.78 | Selectivity | 840777 | 3568 | bNOS | H2O2 |
1.78 | Selectivity | 755901 | 3568 | bNOS | H2O2 |
1.17 | Activity (%) | 866501 | 2586 | nAChRβ-3 | H2O2 |
0.42 | pIC50 (nM) | 710048 | 3772 | mGluR1 | Glu |
3. Materials and Methods
3.1. Computational Methods
3.1.1. ALMA-Entropy Models
3.1.2. CHEMBL Dataset
3.2. Experimental Methods: Chemistry
3.2.1. Synthesis of 1,2-Rasagiline Derivatives
3.2.2. Reaction of Carbamylation
3.3. Experimental Methods: Biology
3.3.1. Culture of Rat Cortical Neurons
3.3.2. Measurement of Neuronal Viability
4. Conclusions
Acknowledgments
Author Contributions
Supplementary Information
Conflict of Interest
References
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Durán, F.J.R.; Alonso, N.; Caamaño, O.; García-Mera, X.; Yañez, M.; Prado-Prado, F.J.; González-Díaz, H. Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates. Int. J. Mol. Sci. 2014, 15, 17035-17064. https://doi.org/10.3390/ijms150917035
Durán FJR, Alonso N, Caamaño O, García-Mera X, Yañez M, Prado-Prado FJ, González-Díaz H. Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates. International Journal of Molecular Sciences. 2014; 15(9):17035-17064. https://doi.org/10.3390/ijms150917035
Chicago/Turabian StyleDurán, Francisco J. Romero, Nerea Alonso, Olga Caamaño, Xerardo García-Mera, Matilde Yañez, Francisco J. Prado-Prado, and Humberto González-Díaz. 2014. "Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates" International Journal of Molecular Sciences 15, no. 9: 17035-17064. https://doi.org/10.3390/ijms150917035