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Gene & Protein in Disease Inhibition of SOD1 in diseases

Disrupting SOD1 activity has been shown to inhibit cell binding interaction. Meanwhile, a high covalent binding
growth and enhance lipid accumulation in nasopharyngeal energy suggests the formation of strong covalent bonds
carcinoma, a commonly occurring cancer with the highest between the binding partners, which may indicate a stable
incidence of malignant proliferation among head and binding complex. However, it is important to note that
neck cancers. SOD1 mRNA has been reported to be in drug design, covalent binding can sometimes lead to
40
significantly increased in head and neck cancer tissues, undesirable side effects, necessitating careful consideration.
according to data from the Oncomine microarray Moreover, a high hydrogen-bonding correction suggests
database (https://www.oncomine.org). Multiple signaling the formation of strong hydrogen bonds between the
pathways, including ERK, NF-κB, and PI3K-Akt, which binding partners, contributing to the specificity and
are essential for the onset and development of cancer, stability of the binding interaction.
can be activated by intracellularly sustained high levels Regarding the compound CID 36791369 – SOD1
of hydrogen peroxide provided by elevated activity and complex, MMGBSA binding energy relies on various
expression of copper/zink-containing SOD1. The use of
SOD1 inhibitors, including LD100, U0126, LY294002, and contributory energies, such as lipophilic, pi-pi, generalized
Born electrostatic solvation, and van der Waals interactions.
BAY117082, has been reported to attenuate some of these High lipophilic energy suggests robust hydrophobic
signaling pathways. 41
interactions, which are important for stabilizing binding
Molecular docking was utilized to assess the binding complexes, especially within hydrophobic pockets of
affinity of the protein with the ligand, facilitating proteins. However, excessively high lipophilic energy
the determination of the binding site and type of might indicate a propensity for non-specific binding
inhibitions. A binding affinity score of ≤ -5.00 kcal·mol to hydrophobic regions. Similarly, high pi-pi packing
-1
indicates a good ligand-protein interaction. A previous correction indicates strong interactions between aromatic
42
computational study utilizing molecular docking and rings, which are essential for stabilizing binding complexes,
MDS has demonstrated that 2,3,5,4’-tetrahydroxystilbene- especially in protein-ligand interactions. Moreover, high
2-O-b-D-glucoside, hesperidin, and hyperoside have high solvation energy may suggest strong interactions between
affinity to mutant SOD1, which is relevant to ALS. 43 the solute and solvent molecules, potentially affecting
MDSs were then conducted to evaluate atomic-level the overall stability of the binding complex. However,
variations in the protein-ligand system and assess the excessively high solvation energy could imply poor
stability of the protein-ligand complex in a dynamic solubility or unfavorable interactions with the solvent.
environment. RMSD values less than 4 Å suggest relatively High van der Waals energy indicates robust, attractive
44
small conformational changes in the complexes during interactions between non-polar groups, contributing to the
the simulation, indicating their stability. In addition, the stability of the binding complex. However, excessively high
45
RMSF is useful for characterizing local changes along the van der Waals energy might lead to non-specific binding
protein chain. Prime MMGBSA provided various energy or aggregation.
properties, reporting energies for the ligand, receptor, and
complex structures, as well as energy differences related 5. Conclusion
to strain and binding. The more negative the score, the This study explored several inhibitors of human SOD1
26
higher the free energy released in complex formation. using enrichment virtual screening, docking, ADME
The total binding free energy confirmed the stability of prediction, and molecular dynamics simulation. Among
the complexes under physiological conditions, indicating the 42 compounds selected for thorough analyses, five
their reasonable stability. A high total energy indicates a demonstrated favorable ADME properties, promoting
strong binding affinity between the molecules. However, BBB permeability and high GIA. In addition, seven
the interpretation depends on the specific contributions of compounds exhibited binding affinity values of less
individual energy terms and the context of the study. than -5.00 kcal·mol for SOD1, indicating robust
-1
In this study, the MMGBSA binding energy of the interaction. Specifically, compounds SN5, SN6, SN7, SN12,
compound CID 30935 – SOD1 complex is influenced by and SN25 emerged as potential SOD1inhibitors. Further
several contributing energies, such as Coulomb, covalent, research will be necessary to investigate the therapeutic
and hydrogen bonding. A high Coulomb energy indicates effectiveness of these top five compounds in both in vitro
robust electrostatic interactions between charged groups, and in vivo settings against SOD1.
suggesting either strong attraction or repulsion between Acknowledgments
the binding partners. Understanding these interactions is
significant for elucidating the stability or specificity of the None.

Volume 3 Issue 2 (2024) 9 doi: 10.36922/gpd.3042