In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is regarded as a fatal neurodegenerative disease that is featured by progressive damage of the upper and lower motor neurons. To date, over 45 genes have been found to be connected with ALS pathology. The aim of this work was to computationally identify unique sets of protein hydrolysate peptides that could serve as therapeutic agents against ALS. Computational methods which include target prediction, protein-protein interaction, and peptide-protein molecular docking were used. The results showed that the network of critical ALS-associated genes consists of ATG16L2, SCFD1, VAC15, VEGFA, KEAP1, KIF5A, FIG4, TUBA4A, SIGMAR1, SETX, ANXA11, HNRNPL, NEK1, C9orf72, VCP, RPSA, ATP5B, and SOD1 together with predicted kinases such as AKT1, CDK4, DNAPK, MAPK14, and ERK2 in addition to transcription factors such as MYC, RELA, ZMIZ1, EGR1, TRIM28, and FOXA2. The identified molecular targets of the peptides that support multi-metabolic components in ALS pathogenesis include cyclooxygenase-2, angiotensin I-converting enzyme, dipeptidyl peptidase IV, X-linked inhibitor of apoptosis protein 3, and endothelin receptor ET-A. Overall, the results showed that AGL, APL, AVK, IIW, PVI, and VAY peptides are promising candidates for further study. Future work would be needed to validate the therapeutic properties of these hydrolysate peptides by in vitro and in vivo approaches.

In Silico Analysis of Individual Fractions of Bovine Casein as Precursors of Bioactive Peptides—Influence of Post-Translational Modifications

“…In the case of peptides built from unmodified protein amino acids, proteolytic enzymes serve as the main group of potentially interacting proteins [93]. The highest probability of peptide-protein interactions, presented in Table 4, is lower than the analogous probability predicted for the peptides described in previous works [92][93][94]. The difference in the probability of interactions with proteins noted between the peptides built of the nonmodified amino acids and phosphopeptides may stem from two reasons.…”

Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols

“…While docking is undoubtedly a leading technique, it still faces persistent challenges [ 4 , 5 , 6 , 7 , 8 , 9 ], especially when it comes to large, flexible peptide ligands. However, peptides mediate up to 40% of naturally occurring protein–protein interactions and play a central role in various cellular processes, including signal transduction, transcriptional regulation, immune response, and oncology [ 10 , 11 , 12 , 13 , 14 ]. Structural models of peptide–protein complexes have been used to design inhibitory peptides and peptidomimetics that modulate protein–protein interactions involved in various disease pathways [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

“…However, peptides mediate up to 40% of naturally occurring protein–protein interactions and play a central role in various cellular processes, including signal transduction, transcriptional regulation, immune response, and oncology [ 10 , 11 , 12 , 13 , 14 ]. Structural models of peptide–protein complexes have been used to design inhibitory peptides and peptidomimetics that modulate protein–protein interactions involved in various disease pathways [ 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. In addition to their high specificity and relatively low toxicity [ 21 , 22 , 23 , 24 ], peptides have been able to successfully target protein complexes such as transcription factors, which were considered undruggable by small molecules due to their huge structures and stable state [ 25 , 26 ].…”