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.
References
  1. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97-112. doi: 10.1146/annurev.bi.64.070195.000525

 

  1. Juarez JC, Manuia M, Burnett ME, et al. Superoxide dismutase 1 (SOD1) is essential for H2O2-mediated oxidation and inactivation of phosphatases in growth factor signaling. Proc Natl Acad Sci U S A. 2008;105(20):7147-7152. doi: 10.1073/pnas.0709451105

 

  1. Ticozzi N, Tiloca C, Morelli C, et al. Genetics of familial amyotrophic lateral sclerosis. Arch Ital Biol. 2011;149(1):65-82. doi: 10.4449/aib.v149i1.1262

 

  1. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: What do we really know? Nat Rev Neurol. 2011;7(11):603-615.doi: 10.1038/nrneurol.2011.150

 

  1. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/ Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59-62. doi: 10.1038/362059a0

 

  1. Sibilla C, Bertolotti A. Prion properties of SOD1 in amyotrophic lateral sclerosis and potential therapy. Cold Spring Harbor Perspect Biol. 2017;9(10):a024141. doi: 10.1101/cshperspect.a024141

 

  1. Ligon LA, LaMonte BH, Wallace KE, Weber N, Kalb RG, Holzbaur EL. Mutant superoxide dismutase disrupts cytoplasmic dynein in motor neurons. Neuroreport. 2005;16(6):533-536. doi: 10.1097/00001756-200504250-00002

 

  1. Zhang F, Strom AL, Fukada K, Lee S, Hayward LJ, Zhu H. Interaction between familial amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants and the dynein complex. J Biol Chem. 2007;282(22):16691-16699. doi: 10.1074/jbc.M609743200

 

  1. Elchuri S, Oberley TD, Qi W, et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene. 2005;24(3):367-380. doi: 10.1038/sj.onc.1208207

 

  1. Busuttil RA, Garcia AM, Cabrera C, et al. Organ-specific increase in mutation accumulation and apoptosis rate in CuZn-superoxide dismutase-deficient mice. Cancer Res. 2005;65(24):11271-11275. doi: 10.1158/0008-5472.CAN-05-2980

 

  1. Ho YS, Gargano M, Cao J, Bronson RT, Heimler I, Hutz RJ. Reduced fertility in female mice lacking copper-zinc superoxide dismutase. J Biol Chem. 1998;273(13):7765-7769. doi: 10.1074/jbc.273.13.7765

 

  1. Blander G, De Oliveira RM, Conboy CM, Haigis M, Guarente L. Superoxide dismutase 1 knock-down induces senescence in human fibroblasts. J Biol Chem. 2003;278(40):38966-38969. doi: 10.1074/jbc.M307146200

 

  1. Somwar R, Erdjument-Bromage H, Larsson E, et al. Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines. Proc Natl Acad Sci U S A. 2011;108(39):16375-16380. doi: 10.1073/pnas.1113554108

 

  1. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605-D612. doi: 10.1093/nar/gkaa1074

 

  1. Backman TW, Cao Y, Girke T. ChemMine tools: An online service for analyzing and clustering small molecules. Nucleic Acids Res. 2011;39:W486-W491. doi: 10.1093/nar/gkr320

 

  1. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. doi: 10.1038/srep42717

 

  1. Fatoki T, Chukwuejim S, Ibraheem O, et al. Harmine and 7,8-dihydroxyflavone synergistically suitable for amyotrophic lateral sclerosis management: An in silico study. Res Results Pharmacol. 2022;8(3):49-61. doi: 10.3897/rrpharmacology.8.83332

 

  1. Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-2791. doi: 10.1002/jcc.21256

 

  1. Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-461. doi: 10.1002/jcc.21334

 

  1. Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock vina 1.2.0: New docking methods, expanded force field, and python bindings. J Chem Inf Model. 2021;61(8):3891-3898. doi: 10.1021/acs.jcim.1c00203

 

  1. Tao A, Huang Y, Shinohara Y, Caylor ML, Pashikanti S, Xu D. ezCADD: A rapid 2D/3D visualization-enabled web modeling environment for democratizing computer-aided drug design. J Chem Inf Model. 2019;59(1):18-24. doi: 10.1021/acs.jcim.8b00633

 

  1. Schrödinger. Schrödinger Release 2018-3. Desmond Molecular Dynamics System. New York: D.E. Shaw Research, Maestro Desmond Interoperability Tools, Schrödinger; 2018.

 

  1. Ali I, Iqbal MN, Ibrahim M, Haq IU, Alonazi WB, Siddiqi AR. Computational exploration of novel ROCK2 inhibitors for cardiovascular disease management; insights from high-throughput virtual screening, molecular docking, DFT and MD simulation. PLoS One. 2023;18(11):e0294511. doi: 10.1371/journal.pone.0294511

 

  1. Fatoki TH, Faleye BC, Nwagwe OR, et al. Friedelin could moderately modulate human carbonic anhydrases: An in silico study. Bioint Res Appl Chem. 2024;14(2):49. doi: 10.33263/BRIAC142.049

 

  1. Fatoki TH. Effect of pH on structural dynamics of HMG-CoA reductase and binding affinity to β-sitosterol. J Biomol Struct Dyn. 2023;41(10):4398-4404. doi: 10.1080/07391102.2022.2067240

 

  1. Schrödinger. What do All the Prime MM-GBSA Energy Properties Mean? 2019. Available from: https://www. schrodinger.com/kb/1875 [Last accessed on 2023 Nov 20].

 

  1. Richarme G, Mihoub M, Dairou J, Bui LC, Leger T, Lamouri A. Parkinsonism-associated protein DJ-1/Park7 is a major protein deglycase that repairs methylglyoxal- and glyoxal-glycated cysteine, arginine, and lysine residues. J Biol Chem. 2015;290(3):1885-1897. doi: 10.1074/jbc.M114.597815

 

  1. Perini GF, Ribeiro GN, Pinto Neto JV, Campos LT, Hamerschlak N. BCL-2 as therapeutic target for hematological malignancies. J Hematol Oncol. 2018;11(1):65. doi: 10.1186/s13045-018-0608-2

 

  1. Sugiyama T, Murao N, Kadowaki H, et al. ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function. iScience. 2021;24(7):102758. doi: 10.1016/j.isci.2021.102758

 

  1. Olivo E, La Chimia M, Ceramella J, et al. Moving beyond the Tip of the Iceberg: DJ-1 implications in cancer metabolism. Cells. 2022;11(9):1432. doi: 10.3390/cells11091432

 

  1. Fatoki TH, Chukwuejim S, Udenigwe CC, Aluko RE. In silico exploration of metabolically active peptides as potential therapeutic agents against amyotrophic lateral sclerosis. Int J Mol Sci. 2023;24(6):5828. doi: 10.3390/ijms24065828

 

  1. Blokhuis AM, Groen EJ, Koppers M, Van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(6):777-794. doi: 10.1007/s00401-013-1125-6

 

  1. Lu H, Zhou Q, He J, et al. Recent advances in the development of protein-protein interactions modulators: Mechanisms and clinical trials. Signal Transd Targeted Ther. 2020;5:213. doi: 10.1038/s41392-020-00315-3

 

  1. Kuzmanov U, Emili A. Protein-protein interaction networks: Probing disease mechanisms using model systems. Genome Med. 2013;5(4):37. doi: 10.1186/gm441

 

  1. National Center for Biotechnology Information. PubChem Patent Summary for US-2015337018-A1. Available from: https://pubchem.ncbi.nlm.nih.gov/patent/US-2015337018-A1 [Last accessed on 2023 Dec 04].

 

  1. Juarez JC, Betancourt O Jr., Pirie-Shepherd SR, et al. Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1. Clin Cancer Res. 2006;12(16):4974-4982. doi: 10.1158/1078-0432.CCR-06-0171

 

  1. Fatoki TH, Awofisayo OA, Ibraheem O, Oyedele AS, Akinlolu OS. In silico investigation of first-pass effect on selected small molecule excipients and structural dynamics of P-glycoprotein. Bioinform Biol Insights. 2020;14:1177932220943183. doi: 10.1177/11779322209431

 

  1. Martin P, Giardiello M, McDonald TO, Rannard SP, Owen A. Mediation of in vitro cytochrome P450 activity by common pharmaceutical excipients. Mol Pharm. 2013;10:2739-2748. doi: 10.1021/mp400175n

 

  1. Antonyuk S, Strange RW, Hasnain SS. Structural discovery of small molecule binding sites in Cu-Zn human superoxide dismutase familial amyotrophic lateral sclerosis mutants provides insights for lead optimization. J Med Chem. 2010;53(3):1402-1406. doi: 10.1021/jm9017948

 

  1. Li S, Fu L, Tian T, et al. Disrupting SOD1 activity inhibits cell growth and enhances lipid accumulation in nasopharyngeal carcinoma. Cell Commun Signal. 2018;16:28. doi: 10.1186/s12964-018-0240-3

 

  1. Li X, Chen Y, Zhao J, et al. The specific inhibition of SOD1 selectively promotes apoptosis of cancer cells via regulation of the ROS signaling network. Oxid Med Cell Longev. 2019;2019:9706792. doi: 10.1155/2019/9706792

 

  1. Wong F, Krishnan A, Zheng EJ, et al. Benchmarking AlphaFold-enabled molecular docking predictions for antibiotic discovery. Mol Syst Biol. 2022;18(9):e11081. doi: 10.15252/msb.202211081

 

  1. Huang HJ, Chang TT, Chen HY, Chen CY. Finding inhibitors of mutant superoxide dismutase-1 for amyotrophic lateral sclerosis therapy from traditional Chinese medicine. Evid Based Complement Alternat Med. 2014;2014:156276. doi: 10.1155/2014/156276

 

  1. Fatoki TH. Human adenovirus DNA polymerase is evolutionarily and functionally associated with human telomerase reverse transcriptase based on in silico molecular characterization that implicate abacavir and zidovudine. Front Bioinform. 2023;3:1123307. doi: 10.3389/fbinf.2023.1123307

 

  1. Fatoki TH, Balogun CT, Oluwadare OT, et al. In silico evaluation of nutri-pharmacological potentials of phytochemicals in sorghum (Sorghum bicolor) grains. J Food Bioact. 2023;23:18354. doi: 10.31665/JFB.2023.18354
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