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Brain & Heart Lipids in ALS: Bad and beneficial

mechanics/generalized born surface area (MMGBSA) and CYP3A4. The predicted toxicity for these four
calculations were performed to determine the binding free compounds indicated that the average lethal dose (LD )
50
)
energy (ΔG bind 23,26,28 as follows: is as follows: Rotenone, 3 mg/kg; valproic acid, 670 mg/
kg; resveratrol, 1560 mg/kg; and 4-hydroxynonenal
MMGBSA ΔG bind = ΔG Coulomb + ΔG Covalent + ΔG Hbond + 1925 mg/kg. Moreover, rotenone could potentially exert
ΔG Lipo + ΔG Packing + ΔG SolvGB + ΔG vdW (I) immunotoxic effects, while valproic acid has the potential
for hepatotoxicity (Table 3).
3. Results
Target prediction results of the four selected
The disease-to-lipids analysis identified 20 lipid compounds BBB permeant compounds (Table 4) suggest that
that are correlated with ALS. These lipid compounds 4-hydroxynonenal has good target precision for solute
are predominantly recognized as potential inhibitors carrier organic anion transporter family member 2A1,
belonging to the functional class of vitamins, antibiotics, all-trans-retinol dehydrogenase (NAD[+]) (ADH7),
organic acids, and phytochemicals (Table 1). and alkaline ceramidase 2 (ACER2); resveratrol has
Results from the pharmacokinetic prediction revealed good target precision for nuclear factor erythroid
that only four compounds are permeable through the 2-related factor 2, amyloid-beta precursor protein,
blood–brain barrier (BBB), that is, 4-hydroxynonenal, and transthyretin; rotenone has good target precision
resveratrol, rotenone, and valproic acid, while other for cytochrome P450 2C19 (CYP2C19) and NADH-
compounds were predicted to be non-permeable ubiquinone oxidoreductase chain 4 (MT-ND4); valproic
through the BBB as singular entities (Table 2). These acid has good target precision for glutamate-cysteine ligase
four compounds have high gastrointestinal absorption catalytic subunit, mast cell carboxypeptidase A, glutamate
and moderate solubility, and they are not substrates carboxypeptidase 2 (FOLH1), and glutamate receptor
for p-glycoprotein. However, resveratrol and rotenone ionotropic, kainate 1. The results were ranked based on
could also inhibit various cytochromes, such as CYP2C9 P-value and the maximum Tanimoto coefficient (MTC),

Table 1. Lipid‑based compounds obtained from the LipiDisease web server for amyotrophic lateral sclerosis (MeSH unique ID:
D000690)
SN Ligands PubChem CID P FDR
1 4-Aminobutanoic acid 119 1.53E-25 3.35E-25
2 Minocycline 54675783 1.29E-20 2.68E-20
3 Coenzyme Q10 5281915 1.83E-14 3.55E-14
4 2S-Amino-3S-methylpentanoic acid 6306 5.84E-14 1.13E-13
5 Pyruvic acid 1060 3.23E-11 5.98E-11
6 Alpha-tocopherol 14985 7.36E-11 1.36E-10
7 4-Hydroxynonenal 5283344 8.88E-10 1.61E-09
8 Succinic acid 1110 3.78E-08 6.66E-08
9 Acetic acid 176 9.56E-08 1.67E-07
10 Malonic acid 867 3.01E-06 5.09E-06
11 Resveratrol 445154 5.16E-06 8.67E-06
12 Lipoic acid 6112 5.67E-05 9.25E-05
13 Propan-2-one 180 0.000186 0.000298
14 Rotenone 6758 0.000418 0.000662
15 Valproic acid 3121 0.000649 0.001021
16 Deoxycholic acid 222528 0.001557 0.002412
17 Prostaglandin E2 5280360 0.002854 0.004367
18 Hematoxylin 442514 0.019571 0.028625
19 Beta-carotene 5280489 0.024258 0.035251
20 Epigallocatechin 3-gallate 65064 0.029872 0.043105
Abbreviations: CID: Compound identifier; FDR: False discovery rate; MeSH: Medical subject headings; SN: Serial number.

Volume 2 Issue 3 (2024) 3 doi: 10.36922/bh.2976