AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.3042
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ORIGINAL RESEARCH ARTICLE

Rational virtual screening, ADME, and molecular simulation studies of potential inhibitors of human superoxide dismutase 1 in a dysfunctional antioxidant system

Ayodele Sunday Alonge1 ,  Toluwase Hezekiah Fatoki2* ,  Iseoluwa Isaac Ajayi1 ,  Ibrahim Olabayode Saliu3 ,  Stanley Chukwuejim4 ,  Courage Dele Famusiwa5 ,  Oluwafijimi Adetuyi4 ,  Ohunene Esther Joseph1
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1 Department of Biological Sciences, School of Life Science, Bamidele Olumilua University of Education, Science and Technology, Ikere, Ekiti State, Nigeria
2 Applied Bioinformatics Laboratory, Department of Biochemistry, Faculty of Science, Federal University Oye Ekiti, Oye, Ekiti State, Nigeria
3 Department of Genetics, School of Medicine, Washington University St. Louis, Missouri, United States of America
4 Enzymology Laboratory, Department of Biochemistry, Faculty of Science, Federal University Oye Ekiti, Oye, Ekiti State, Nigeria
5 Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Faculty of Science, Federal University Oye Ekiti, Oye, Ekiti State, Nigeria
GPD 2024, 3(2), 3042 https://doi.org/10.36922/gpd.3042
Submitted: 28 February 2024 | Accepted: 18 April 2024 | Published: 5 June 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Superoxide dismutase 1 (SOD1), a copper-dependent enzyme, facilitates the conversion of superoxide anions into hydrogen peroxide and oxygen, thereby regulating superoxide levels. Dysfunctions in SOD1 have been linked to neurodegenerative disorders such as amyotrophic lateral sclerosis, as well as liver and lung cancers. This study aimed to identify SOD1 modulators using in silico rational virtual enrichment screening, pharmacokinetics, docking, and molecular dynamic simulation (MDS). The findings yielded 38 compounds, predominantly exhibiting high gastrointestinal absorption but mostly non-permeable across the blood–brain barrier, with few exhibiting inhibitory effects on selected cytochrome P450s. Molecular docking revealed that compound 1 (PubChem CID: 36791369) exhibited the highest binding affinity (−6.771 kcal·mol-1), followed by compound 19 (PubChem CID: 30935) with −6.468 kcal·mol-1, and compound 20 (PubChem CID: 135744521) with −5.978 kcal·mol-1. MDS and molecular mechanics/generalized Born surface area analysis indicated that the compound CID 36791369 – SOD1 complex and compound CID 30935 – SOD1 complex remained stable and energetically favorable under simulated physiological conditions at 0 ns and 100 ns. In conclusion, this study identified 38 compounds, among which compounds SN5, SN6, SN7, SN12, and SN25 emerged as potential inhibitors of SOD1 based on overall analyses. Further, research will be necessary to investigate the therapeutic effectiveness of these top five compounds in vitro and in vivo against SOD1.

Keywords
SOD1
Cancer
Amyotrophic lateral sclerosis
Novel inhibitors
Pharmacokinetics
Molecular docking
Molecular dynamics simulation
Funding
None.
Conflict of interest
No conflicts of interest to declare.
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