In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein
Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, SOD1 binding ligand...
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Published in | Pharmaceutics Vol. 15; no. 4; p. 1095 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
MDPI AG
29.03.2023
MDPI |
Subjects | |
Online Access | Get full text |
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Summary: | Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, SOD1 binding ligand 1 (SBL-1) was shown to inhibit in vitro the oxidation of a critical residue for SOD1 aggregation, which is a central event in ALS-related neurodegeneration. In this work, we investigated the interactions between SOD1 wild-type and its most frequent variants, i.e., A4V (NP_000445.1:p.Ala5Val) and D90A (NP_000445.1:p.Asp91Val), with SBL-1 using molecular dynamics (MD) simulations. The pharmacokinetics and toxicological profile of SBL-1 were also characterized in silico. The MD results suggest that the complex SOD1-SBL-1 remains relatively stable and interacts within a close distance during the simulations. This analysis also suggests that the mechanism of action proposed by SBL-1 and its binding affinity to SOD1 may be preserved upon mutations A4V and D90A. The pharmacokinetics and toxicological assessments suggest that SBL-1 has drug-likeness characteristics with low toxicity. Our findings, therefore, suggested that SBL-1 may be a promising strategy to treat ALS based on an unprecedented mechanism, including for patients with these frequent mutations. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1999-4923 1999-4923 |
DOI: | 10.3390/pharmaceutics15041095 |