Page 73 - BH-2-3

Brain & Heart Lipids in ALS: Bad and beneficial

1. Introduction to extract metabolic and medicinal lipids, along with their
corresponding associated P-values.
Amyotrophic lateral sclerosis (ALS) is a fatal, currently
incurable neurodegenerative disease that affects the 2.2. Target prediction analysis
upper motor neurons in the brain and lower motor The PubChem database (https://pubchem.ncbi.nlm.nih.
neurons in the spinal cord and it progresses gradually, gov/) was used to obtain the chemical structures of 20
culminating in immobility and eventual death due to identified lipid-based compounds in SMILES format.
respiratory failure. Neurons acquire monocarboxylates Subsequently, target prediction was carried out on the
1-4
from the brain through monocarboxylate transporters, similarity ensemble approach (SEA) search server (http://
which are essential for energy metabolism in mitigating www.sea.bkslab.org/) using the SMILES notation of each
17
neurodegenerative diseases. A study indicated a compound.
significant decrease in the expression of sodium-coupled
monocarboxylate transporter 1 (MCT1) and MCT1 in the 2.3. In silico absorption, distribution, metabolism,
motor neurons of ALS (hSOD1G93A) mice compared to excretion, and toxicity (ADMET) prediction
wild-type mice. 5
The SMILES notation of the compounds was used to
The brain harbors abundant lipids, and anomalies in evaluate the ADMET properties on the SwissADME server
6,7
lipid metabolism are prevalent among ALS patients. (www.swissadme.ch ) and ProTox II web server (https://
18
Various factors influencing cerebrospinal fluid (CSF) tox-new.charite.de/protox_II/).
dynamics in ALS patients include diminished arterial
pulsations, disrupted sleep, compromised respiratory 2.4. Molecular docking
function, and abnormal aquaporin 4 expression. A study The SMILES representation of the ligands was processed
8
has identified apolipoprotein B-100 in the CSF of sporadic and saved in.mol format. Subsequently, PyMol software
ALS as a probable agent responsible for motor neuron was employed to convert the ligand files from.mol to.pdb
debility and degeneration, as well as dysregulation of TDP- format. Before docking, the ligands’ 3D structures were
43 translocation. 9 optimized using ACDLab/Chemsketch software. The
Furthermore, research indicates clear connections 3D AlphaFold structures and subcellular locations of the
between metabolic components and ALS pathogenesis, proteins were directly retrieved from the UniProt database
suggesting the potential for additional molecular targets (https://www.uniprot.org). The preparation of ligand and
for therapeutic interventions. 4,10,11 Numerous studies have protein docking files was performed using AutoDock
19
delved into lipid profiles in biofluids of ALS patients, Tools (ADT) v1.5.6., and the docking was implemented
pinpointing dysregulation of sphingolipids, including using AutoDock Vina v1.2.3, 20,21 following previous
sphingomyelin and glycosphingolipids. 12-14 An extensive protocols. 22,23 Subsequently, ezLigPlot on the ezCADD web
24
lipidomic investigation in SOD1 G93A transgenic rats server (http://dxulab.org/software) was used to visualize
revealed minimal lipid alterations in the motor cortex, the binding interactions.
contrasting with substantial changes in the lipidome of the 2.5. Molecular dynamics simulations (MDS)
lumbar spinal cord. In addition, a recent study highlighted
15
significant lipid dysregulation in a TDP-43 Q331K mouse Ligand-protein complexes with the highest docking
16
model of ALS. Herein, this study investigates lipid-based binding affinity were used for this analysis. Each complex
compounds linked to ALS, assessing pharmacokinetics, was preprocessed using Maestro’s Protein Preparation
molecular binding affinities, and dynamics to enhance Wizard, which included optimization and energy
understanding of the disease and develop effective minimization. Desmond software by Schrödinger LLC was
therapeutics. used to conduct a system simulation of 100 ns. 23,25,26 The
system setup includes an OPLS-2005 force field, which is
2. Methods an orthorhombic box with a TIP3P water model containing
0.15 M NaCl counter ions to establish physiological
2.1. Lipids dataset preparation conditions, maintained at 300 K temperature and 1 atm
27
The term “Amyotrophic Lateral Sclerosis” was queried in pressure for the simulation. The models were relaxed before
the medical subject headings (MeSH) 2023 (www.meshb. simulation, and trajectories were saved after every 100 ps.
nlm.nih.gov/search) to obtain the unique ID (D000690). The post-simulation trajectory analysis was conducted
This MeSH unique ID was then employed for disease- to determine the root-mean-square fluctuation (RMSF),
to-lipids analysis on the LipiDisease web server (www. root-mean-square deviation (RMSD), and protein-
cbdm-01.zdv.uni-mainz.de:3838/piyusmor/LipiDisease/) ligand interaction profile. In addition, prime molecular

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