Protein Targets for preventing/alleviating Diabetic neuropathy

No Target proteins Standard Drugs

1 Aldose reductase Epalrestat Inhibitor
2 RAGEs (receptor for AGEs) FPS-ZM1 Inhibitor
3 Protein kinase C-β LY333531 Inhibitor
4 Extracellular signal-regulated SCH772984 compound Inhibitor
kinase (ERK) 1/2
5 2, c-Jun N-terminal kinases (JNK) Anthrapyrazolone SP600125 Inhibitor
1-3
6 p38 MAPK Pamapimod Inhibitor
(R-1503, Ro4402257)

Phytochemical compounds as prospective ligands for protein involving in diabetic neuropathy

Result of UPLC-MS analysis of Vitis gracilis decoction

Mol
RT Measured
NO
Time
% area
mass
Formula [M- Compound name
H] +
1 1.26 222.0186 C10H6O6 2,4,5-trihydroxy-7,8-dioxonaphthalen-1-olate
2 1.37 7.49 144.1019 C8H16O2 2-propylpentanoate, valproic acid
3 1.44 215.0661 C13H11O3 phenyl 2-hydroxybenzoate, Phenyl salicylate
4 2.29 3.05 167.0712 C5H11O6 Ribonic acid, 2,3,4,5-tetrahydroxypentanoic acid
5 2.57 2.46 167.0693 C9H11O3 Ethylparaben
(2S,3S)-2,3-Dihydro-2-[2-hydroxy-4-(beta-D-
glucopyranosyloxy) phenyl]-3-(3,5-dihydroxyphenyl)-
6 3.47 1.65 795.2471 C40H43O17
4-[2-[4-(beta-D-
glucopyranosyloxy)phenyl]ethenyl]benzofuran-6-ol
7 4.04 16.02 118.0532 C5H10O3 3-hydroxy-3methylbutanoate,
8 4.57 2.33 181.0866 C10H13O3 Propyl 4-hydroxybenzoate
9 5.06 2.85 333.1321 C21H17O4 3',4'-dimethoxy-alpha-naphthoflavone
(3b,16a,20R)-25-Acetoxy-3,16,20,22-tetrahydroxy-5-
10 5.45 8.35 711.4428 C38H63O12
cucurbiten-11-one 3-glucoside
11 5.89 5.89 60.0039 C2H4O2 Acetic acid
6,6,9-trimethyl-3-(3-methyloctan-2-yl)-7,8,9,10-
12 5.98 371.3079 C25H39O2
tetrahydrobenzo[c]chromen-1-ol
14 7.45 191.1267 C9H19O4 Dipropyleneglycol methyl ether acetate
15 7.54 10.7 494.1963 C39H26 1-Naphthylbis(9-anthryl)methylcation
16 7.61 527.1743 C38H23O3 4-phenylethynylnaphthalic anhydride
[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-
18 8.51 0.8 457.187 C21H29O11 [[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-
yl]oxymethyl]oxan-2-yl] (E)-3-phenylprop-2-enoate
19 9.25 1.74 273.1143 C12H17O7 Arbutin
5-[6-hydroxy-5-(3-methylbut-2-enyl)-1-benzofuran-2-
20 9.72 1.75 311.1432 C19H19O4
yl]benzene-1,3-diol
 ethane;2-O-[3-(2-
methoxycarbonylcyclohexanecarbonyl)oxy-2-
methylpropyl] 1-O-methyl cyclohexane-1,2-
21 9.8 1027.7008 C56H99O16 dicarboxylate;7-oxabicyclo[4.1.0]heptan-3-ylmethyl 4-
hydroxy-3-methylcyclohexane-1-carboxylate;1-[[4-
(oxiran-2-
ylmethoxymethyl)cyclohexyl]methoxy]butan-2-ol
22 10.51 0.62 337.3269 C22H41O2 (13Z,16Z)-docosa-13,16-dienoic acid
23 11.15 2.49 550.3538 C28H45O8 Carthamoleusterone
5-propan-2-yl-1,3-benzodioxole;1-propan-2-
ylnaphthalene;2-propan-2-ylnaphthalene;1-propan-2-
24 13.41 0.79 853.5585 C61H73O3
ylnaphthalen-2-ol;1,3,5-trimethyl-2-propan-2-
ylbenzene
25 15.21 5.63 645.6215 C39H81O6 dodecanoic acid;propane
26 16.13 5.36 411.3606 C29H47O 4,4-Dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol
27 16.99 2.8 637.3809 C42H53O5 Norethindrone acetate and ethinyl estradiol
3-[(2-carboxyacetyl)oxymethoxy]-3-oxopropanoic
acid;3-[[3-[5-[3-[(2-carboxyacetyl)oxymethoxy]-3-
28 17.36 861.1624 C31H41O28 oxopropanoyl]oxy-2,4-dihydroxypentoxy]-3-
oxopropanoyl]oxymethoxy]-3-oxopropanoic acid;2-
(oxiran-2-ylmethyl)oxirane

Biologycal activity Protein

Compound name
2,4,5-trihydroxy-7,8-dioxonaphthalen-1-olate
Deoxyribosa-Phosphate Aldolase reductase
aldolase inhibitor (pi 0,003)

Diabetic neuropathy -Aldolase reductase,

treatment (pi 0,003) -RAGEs (receptor for
AGEs)
2-propylpentanoate, valproic acid -Protein kinase C-β
- Extracellular signal-
regulated kinase (ERK) ½
-2, c-Jun N-terminal
kinases (JNK) 1-3
- p38 MAPK

phenyl 2-hydroxybenzoate, Phenyl salicylate

Ribonic acid, 2,3,4,5-tetrahydroxypentanoic acid
MAPK inhibitor (pi 0,014) P38 MAPK

Diabetic neuropathy -Aldolase reductase,

treatment (pi 0,010) -RAGEs (receptor for
AGEs)
-Protein kinase C-β
Ethylparaben - Extracellular signal-
regulated kinase (ERK) ½
-2, c-Jun N-terminal
kinases (JNK) 1-3
- p38 MAPK

(2S,3S)-2,3-Dihydro-2-[2-hydroxy-4-(beta-D-
glucopyranosyloxy) phenyl]-3-(3,5-
dihydroxyphenyl)-4-[2-[4-(beta-D-
glucopyranosyloxy)phenyl]ethenyl]benzofuran-6-
ol
Protein kinase C-β Protein kinase C-β
inhibitor (pi 0,010)
3-hydroxy-3methylbutanoate,
2, c-Jun N-terminal kinases 2, c-Jun N-terminal kinases
(JNK) 1-3 (pi 0,60) (JNK) 1-3
Propyl 4-hydroxybenzoate Diabetic neuropathy
treatment (pi 0,010) -Aldolase reductase,
-RAGEs (receptor for
AGEs)
-Protein kinase C-β
- Extracellular signal-
regulated kinase (ERK) ½
-2, c-Jun N-terminal
kinases (JNK) 1-3
- p38 MAPK
 Kinase inhibitor -Protein kinase C-β
- Extracellular signal-
regulated kinase (ERK) ½
3',4'-dimethoxy-alpha-naphthoflavone -2, c-Jun N-terminal
kinases (JNK) 1-3
- p38 MAPK

(3b,16a,20R)-25-Acetoxy-3,16,20,22-tetrahydroxy-
5-cucurbiten-11-one 3-glucoside
Acetic acid
6,6,9-trimethyl-3-(3-methyloctan-2-yl)-7,8,9,10-
tetrahydrobenzo[c]chromen-1-ol
Dipropyleneglycol methyl ether acetate
1-Naphthylbis(9-anthryl)methylcation
4-phenylethynylnaphthalic anhydride
[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-
[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-
methyloxan-2-yl]oxymethyl]oxan-2-yl] (E)-3-
phenylprop-2-enoate
Aldolase reductase inhibitor -Aldolase reductase,
(pi 0,007)
arbutin
Protein kinase C-β Protein kinase C-β
inhibitor (pi 0,010)

5-[6-hydroxy-5-(3-methylbut-2-enyl)-1-
benzofuran-2-yl]benzene-1,3-diol
ethane;2-O-[3-(2-
methoxycarbonylcyclohexanecarbonyl)oxy-2-
methylpropyl] 1-O-methyl cyclohexane-1,2-
dicarboxylate;7-oxabicyclo[4.1.0]heptan-3-
ylmethyl 4-hydroxy-3-methylcyclohexane-1-
carboxylate;1-[[4-(oxiran-2-
ylmethoxymethyl)cyclohexyl]methoxy]butan-2-ol
Diabetic neuropathy
treatment (pi 0,018) -Aldolase reductase,
-RAGEs (receptor for
AGEs)
-Protein kinase C-β
(13Z,16Z)-docosa-13,16-dienoic acid - Extracellular signal-
regulated kinase (ERK) ½
-2, c-Jun N-terminal
kinases (JNK) 1-3
- p38 MAPK

Carthamoleusterone
5-propan-2-yl-1,3-benzodioxole;1-propan-2-
ylnaphthalene;2-propan-2-ylnaphthalene;1-propan-
2-ylnaphthalen-2-ol;1,3,5-trimethyl-2-propan-2-
ylbenzene
dodecanoic acid;propane
4,4-Dimethyl-5alpha-cholesta-8,14,24-trien-3beta-
ol
Norethindrone acetate and ethinyl estradiol
3-[(2-carboxyacetyl)oxymethoxy]-3-oxopropanoic
acid;3-[[3-[5-[3-[(2-carboxyacetyl)oxymethoxy]-3-
oxopropanoyl]oxy-2,4-dihydroxypentoxy]-3-
oxopropanoyl]oxymethoxy]-3-oxopropanoic
acid;2-(oxiran-2-ylmethyl)oxirane

Docking
 Compound Protein
Aldolase r RAGEs kinase C-β ERK JNK MAPK
2-propylpentanoate, valproic acid + + + + + +
Ethylparaben + + + + + +
3-hydroxy-3methylbutanoate + +
Propyl 4-hydroxybenzoate + + + + + +
3',4'-dimethoxy-alpha-naphthoflavone + + + +
arbutin + +
(13Z,16Z)-docosa-13,16-dienoic acid + + + + + +

DOCKING RESULT
 1. Aldolase
No compound Docking
BA RMSD
1 Epalrestat (+) -6,3 0,0
2 2-propylpentanoate, valproic acid -4,8 0,0
3 Ethylparaben -5,3 0,0
4 Propyl 4-hydroxybenzoate -5,5 0,0
5 arbutin -6,6 0,0
6 (13Z,16Z)-docosa-13,16-dienoic acid -4,4 0,0

2. RAGEs
No compound Docking
BA RMSD
1 FPS-ZM1 (+) -9,1 0,0
2 2-propylpentanoate, valproic acid -5,0 0,0
3 Ethylparaben -6,0 0,0
4 Propyl 4-hydroxybenzoate -6,3 0,0
5 (13Z,16Z)-docosa-13,16-dienoic acid -6,4 0,0

3. kinase C-β
No compound Docking
BA RMSD
1 LY333531 (+) -8,7 0,0
2 2-propylpentanoate, valproic acid -4,8 0,0
3 Ethylparaben -5,8 0,0
4 3-hydroxy-3methylbutanoate -5,8 0,0
5 Propyl 4-hydroxybenzoate -5,8 0,0
6 3',4'-dimethoxy-alpha-naphthoflavone -8,2 0,0
7 arbutin -6,8 0,0
8 (13Z,16Z)-docosa-13,16-dienoic acid -5,8 0,0

4. ERK
No compound Docking
 BA RMSD
1 SCH772984 (+) -9,7 0,0
2 2-propylpentanoate, valproic acid -4.6 0,0
3 Ethylparaben -5,6 0,0
4 Propyl 4-hydroxybenzoate -5,5 0,0
5 3',4'-dimethoxy-alpha-naphthoflavone -8,1 0,0
6 (13Z,16Z)-docosa-13,16-dienoic acid -4,3 0,0

5. JNK
No compound Docking
BA RMSD
1 Anthrapyrazolone SP600125 (+) -9,2 0,0
2 2-propylpentanoate, valproic acid -4,9 0,0
3 Ethylparaben -5,7 0,0
4 3-hydroxy-3methylbutanoate -5,6 0,0
5 Propyl 4-hydroxybenzoate -5,9 0,0
6 3',4'-dimethoxy-alpha-naphthoflavone -9,9 0,0
7 (13Z,16Z)-docosa-13,16-dienoic acid -5,8 0,0

6. MAPK
No compound Docking
BA RMSD
1 Pamapimod (R-1503, Ro4402257) (+) -6,6 0,0
2 2-propylpentanoate, valproic acid -5,3 0,0
3 Ethylparaben -5,5 0,0
4 Propyl 4-hydroxybenzoate -7,6 0,0
5 3',4'-dimethoxy-alpha-naphthoflavone -5,5 0,0
6 (13Z,16Z)-docosa-13,16-dienoic acid -6,4 0,0

Ligand Control (+)

Ligand compound yang memiliki nilai lebih tinggi dibandingkan Ligand Control (+)
Ligand compound yang memiliki nilai lebih tinggi dibandingkan Semua Ligand compound
tapi lebih rendah dari pada Ligand Control (+)