In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein

• Published in: Pharmaceutics Vol. 15; no. 4; p. 1095
• Main Authors: Pereira, Gabriel Rodrigues Coutinho, Abrahim-Vieira, Bárbara de Azevedo, de Mesquita, Joelma Freire
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.03.2023; MDPI
• Subjects: ADMET prediction; Amyotrophic lateral sclerosis; Chemical bonds; Drug therapy; Health aspects; Hydrogen bonds; in silico; Ligands; Ligands (Biochemistry); molecular dynamics; Mutation; Oxidation; Pharmacokinetics; Proteins; Simulation; Software; Superoxide dismutase; Testing; Toxicity; Brazil; United States > US; ADMET prediction; in silico; molecular dynamics; amyotrophic lateral sclerosis
• DOI: 10.3390/pharmaceutics15041095
• ISSN: 1999-4923

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.