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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MDPI AG
2023-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/4/1095 |
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| author | Gabriel Rodrigues Coutinho Pereira Bárbara de Azevedo Abrahim-Vieira Joelma Freire de Mesquita |
| author_facet | Gabriel Rodrigues Coutinho Pereira Bárbara de Azevedo Abrahim-Vieira Joelma Freire de Mesquita |
| author_sort | Gabriel Rodrigues Coutinho Pereira |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T04:38:08Z |
| format | Article |
| id | doaj.art-466883845c254e3ea8187d5ffb871368 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T04:38:08Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-466883845c254e3ea8187d5ffb8713682023-11-17T20:52:37ZengMDPI AGPharmaceutics1999-49232023-03-01154109510.3390/pharmaceutics15041095In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I ProteinGabriel Rodrigues Coutinho Pereira0Bárbara de Azevedo Abrahim-Vieira1Joelma Freire de Mesquita2Bioinformatics and Computational Biology Laboratory, Federal University of the State of Rio de Janeiro—UNIRIO, Rio de Janeiro 22290-250, BrazilMolecular Modeling and QSAR Laboratory, Federal University of Rio de Janeiro—UFRJ, Rio de Janeiro 21941-590, BrazilBioinformatics and Computational Biology Laboratory, Federal University of the State of Rio de Janeiro—UNIRIO, Rio de Janeiro 22290-250, BrazilAmyotrophic 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.https://www.mdpi.com/1999-4923/15/4/1095amyotrophic lateral sclerosisin silicomolecular dynamicsADMET prediction |
| spellingShingle | Gabriel Rodrigues Coutinho Pereira Bárbara de Azevedo Abrahim-Vieira Joelma Freire de Mesquita In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein Pharmaceutics amyotrophic lateral sclerosis in silico molecular dynamics ADMET prediction |
| title | In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein |
| title_full | In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein |
| title_fullStr | In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein |
| title_full_unstemmed | In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein |
| title_short | In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein |
| title_sort | in silico analyses of a promising drug candidate for the treatment of amyotrophic lateral sclerosis targeting superoxide dismutase i protein |
| topic | amyotrophic lateral sclerosis in silico molecular dynamics ADMET prediction |
| url | https://www.mdpi.com/1999-4923/15/4/1095 |
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