Screening of Natural Compounds Against SOD1 as a Therapeutic Target
for Amyotrophic Lateral Sclerosis

Sonu      Pahal; Amit      Chaudhary; Sangeeta      Singh

doi:10.2174/1570180819666211228093736

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is an uncommon and progressive neurological illness that predominantly includes the neurons liable for voluntary muscular activities. Starting from weakness or stiffness in muscles, this gradually exploits the strength and ability to speak, eat, move, and even breathe. Its exact mechanism is still not clear, but mutations in the SOD1 gene have been reported to cause ALS, and some studies also found involvement of SOD1 overexpression in the pathogenesis of ALS. As of now, there is no remedy available for its cure.

Objective: The objective of this study is to identify the potential inhibitors for wild type 1HL5, l113T mutant, and A4V mutant of SOD1 (Superoxide Dismutase 1) protein.

Methods: In this study, in silico approaches like virtual screening, molecular docking, pharmacokinetic parameters study, and molecular dynamics simulation were used to identify the best potential inhibitors against wild type and mutant SOD1 protein.

Results: On the basis of binding affinity and binding energy, the top three compounds ZINC000095486263, ZINC000095485989, and ZINC000028462577 were observed as the best compounds. In the case of 1HL5, ZINC000095486263 had the highest binding affinity with docking score - 10.62 Kcal/mol, 1UXM with ZINC000095485989 had the highest docking score -12.03 Kcal/mol, and 4A7V with ZINC000028462577 was found -11.72 Kcal/mol. Further, Molecular Dynamic Simulations (MDS) results showed that the ZINC000095486263, ZINC000095485989, and ZINC000095485956 compounds were formed a stable complex with 1HL5, 1UXM, and 4A7V respectively.

Conclusion: After analyzing the results, we hereby conclude that natural compounds such as ZINC000095486263, ZINC000095485989, and ZINC000095485956 could be used as a potential inhibitor of 1HL5, 1UXM, and 4A7V respectively for ALS treatment and could be used as a drug. Further, In vivo/vitro study of these compounds could be a future direction in the field of drug discovery.

Keywords: Virtual Screening, neurodegenerative disease, molecular docking, ADMET, molecular dynamic simulation, amyotrophic lateral sclerosis

« Previous Next »

Graphical Abstract

[1] 
Batra, G.; Jain, M.; Singh, R.S.; Sharma, A.R.; Singh, A.; Prakash, A.; Medhi, B. Novel therapeutic targets for amyotrophic lateral sclerosis. Indian J. Pharmacol.,  2019, 51(6), 418-425.
[http://dx.doi.org/10.4103/ijp.IJP_823_19] [PMID: 32029967] 
[2] 
Lu, H.; Le, W.D.; Xie, Y-Y.; Wang, X.P. Current therapy of drugs in amyotrophic lateral sclerosis. Curr. Neuropharmacol.,  2016, 14(4), 314-321.
[http://dx.doi.org/10.2174/1570159X14666160120152423] [PMID: 26786249] 
[3] 
Kalmar, B.; Greensmith, L. Cellular chaperones as therapeutic targets in ALS to restore protein homeostasis and improve cellular function. Front. Mol. Neurosci.,  2017, 10, 251.
[http://dx.doi.org/10.3389/fnmol.2017.00251] [PMID: 28943839] 
[4] 
Elliott, E.; Bailey, O.; Waldron, F.M.; Hardingham, G.E.; Chandran, S.; Gregory, J.M. Therapeutic targeting of proteostasis in amyotrophic lateral sclerosis—a systematic review and meta-analysis of preclinical research. Front. Neurosci.,  2020, 14, 511.
[http://dx.doi.org/10.3389/fnins.2020.00511] [PMID: 32523508] 
[5] 
Cleveland, D.W.; Liu, J. Oxidation versus aggregation - How do SOD1 mutants cause ALS? Nat. Med.,  2000, 6(12), 1320-1321.
[http://dx.doi.org/10.1038/82122] [PMID: 11100110] 
[6] 
Takenaka, S.; Fujisawa, T.; Ichijo, H. Apoptosis signal-regulating kinase 1 (ASK1) as a therapeutic target for neurological diseases. Expert Opin. Ther. Targets,  2020, 24(11), 1061-1064.
[http://dx.doi.org/10.1080/14728222.2020.1821648] [PMID: 32930624] 
[7] 
Ralph, G.S.; Radcliffe, P.A.; Day, D.M.; Carthy, J.M.; Leroux, M.A.; Lee, D.C.; Wong, L.F.; Bilsland, L.G.; Greensmith, L.; Kingsman, S.M.; Mitrophanous, K.A.; Mazarakis, N.D.; Azzouz, M. Silencing mutant SOD1 using RNAi protects against neurodegeneration and ex-tends survival in an ALS model. Nat. Med.,  2005, 11(4), 429-433.
[http://dx.doi.org/10.1038/nm1205] [PMID: 15768029] 
[8] 
Abati, E.; Bresolin, N.; Comi, G.; Corti, S. Silence superoxide dismutase 1 (SOD1): A promising therapeutic target for amyotrophic lateral sclerosis (ALS). Expert Opin. Ther. Targets,  2020, 24(4), 295-310.
[http://dx.doi.org/10.1080/14728222.2020.1738390] [PMID: 32125907] 
[9] 
Kumar, S.; Kumar Bhardwaj, V.; Singh, R. Explicit-solvent molecular dynamics simulations revealed conformational regain and aggrega-tion inhibition of I113T SOD1 by Himalayan bioactive molecules. J. Mol. Liq.,  2021, 116798.
[http://dx.doi.org/10.1016/j.molliq.2021.116798] 
[10] 
Israelson, A.; Arbel, N.; Da Cruz, S.; Ilieva, H.; Yamanaka, K.; Shoshan-Barmatz, V.; Cleveland, D.W. Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron,  2010, 67(4), 575-587.
[http://dx.doi.org/10.1016/j.neuron.2010.07.019] [PMID: 20797535] 
[11] 
Graffmo, K.S.; Forsberg, K.; Bergh, J.; Birve, A.; Zetterström, P.; Andersen, P.M.; Marklund, S.L.; Brännström, T. Expression of wild-type human superoxide dismutase-1 in mice causes amyotrophic lateral sclerosis. Hum. Mol. Genet.,  2013, 22(1), 51-60.
[http://dx.doi.org/10.1093/hmg/dds399] [PMID: 23026746] 
[12] 
Jaarsma, D.; Haasdijk, E.D.; Grashorn, J.A.C.; Hawkins, R.; van Duijn, W.; Verspaget, H.W.; London, J.; Holstege, J.C. Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneu-ron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SOD1. Neurobiol. Dis.,  2000, 7(6 Pt B), 623-643.
[http://dx.doi.org/10.1006/nbdi.2000.0299] [PMID: 11114261] 
[13] 
Afshar, P.; Ashtari, N.; Jiao, X.; Rahimi-Balaei, M.; Zhang, X.; Yaganeh, B.; Del Bigio, M.R.; Kong, J.; Marzban, H. Overexpression of human SOD1 leads to discrete defects in the cerebellar architecture in the mouse. Front. Neuroanat.,  2017, 11, 22.
[http://dx.doi.org/10.3389/fnana.2017.00022] [PMID: 28424594] 
[14] 
Wang, L.; Deng, H.X.; Grisotti, G.; Zhai, H.; Siddique, T.; Roos, R.P. Wild-type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse. Hum. Mol. Genet.,  2009, 18(9), 1642-1651.
[http://dx.doi.org/10.1093/hmg/ddp085] [PMID: 19233858] 
[15] 
Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; Duan, Y.; Yu, J.; Wang, L.; Yang, K.; Liu, F.; Jiang, R.; Yang, X.; You, T.; Liu, X.; Yang, X.; Bai, F.; Liu, H.; Liu, X.; Guddat, L.W.; Xu, W.; Xiao, G.; Qin, C.; Shi, Z.; Jiang, H.; Rao, Z.; Yang, H. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature,  2020, 582(7811), 289-293.
[http://dx.doi.org/10.1038/s41586-020-2223-y] [PMID: 32272481] 
[16] 
Zhuang, X.; Zhao, B.; Liu, S.; Song, F.; Cui, F.; Liu, Z.; Li, Y. Noncovalent interactions between superoxide dismutase and flavonoids studied by native mass spectrometry combined with molecular simulations. Anal. Chem.,  2016, 88(23), 11720-11726.
[http://dx.doi.org/10.1021/acs.analchem.6b03359] [PMID: 27760293] 
[17] 
Bhatia, N.K.; Srivastava, A.; Katyal, N.; Jain, N.; Khan, M.A.; Kundu, B.; Deep, S. Curcumin binds to the pre-fibrillar aggregates of Cu/Zn superoxide dismutase (SOD1) and alters its amyloidogenic pathway resulting in reduced cytotoxicity. Biochim. Biophys. Acta,  2015, 1854(5), 426-436.
[http://dx.doi.org/10.1016/j.bbapap.2015.01.014] [PMID: 25666897] 
[18] 
Srinivasan, E.; Rajasekaran, R. Computational investigation of curcumin, a natural polyphenol that inhibits the destabilization and the aggregation of human SOD1 mutant (Ala4Val). RSC Advances,  2016, 6, 102744-102753.
[http://dx.doi.org/10.1039/C6RA21927F] 
[19] 
Srinivasan, E.; Rajasekaran, R. Probing the inhibitory activity of epigallocatechin-gallate on toxic aggregates of mutant (L84F) SOD1 pro-tein through geometry based sampling and steered molecular dynamics. J. Mol. Graph. Model.,  2017, 74, 288-295.
[http://dx.doi.org/10.1016/j.jmgm.2017.04.019] [PMID: 28458007] 
[20] 
Srinivasan, E.; Rajasekaran, R. Comparative binding of kaempferol and kaempferide on inhibiting the aggregate formation of mutant (G85R) SOD1 protein in familial amyotrophic lateral sclerosis: A quantum chemical and molecular mechanics study. Biofactors,  2018, 44(5), 431-442.
[http://dx.doi.org/10.1002/biof.1441] [PMID: 30260512] 
[21] 
Srinivasan, E.; Rajasekaran, R. Quantum chemical and molecular mechanics studies on the assessment of interactions between resveratrol and mutant SOD1 (G93A) protein. J. Comput. Aided Mol. Des.,  2018, 32(12), 1347-1361.
[http://dx.doi.org/10.1007/s10822-018-0175-1] [PMID: 30368622] 
[22] 
Nagano, S.; Takahashi, Y.; Yamamoto, K.; Masutani, H.; Fujiwara, N.; Urushitani, M.; Araki, T. A cysteine residue affects the conforma-tional state and neuronal toxicity of mutant SOD1 in mice: Relevance to the pathogenesis of ALS. Hum. Mol. Genet.,  2015, 24(12), 3427-3439.
[http://dx.doi.org/10.1093/hmg/ddv093] [PMID: 25762155] 
[23] 
Roberts, B.L.; Patel, K.; Brown, H.H.; Borchelt, D.R. Role of disulfide cross-linking of mutant SOD1 in the formation of inclusion-body-like structures. PLoS One,  2012, 7(10), e47838.
[http://dx.doi.org/10.1371/journal.pone.0047838] [PMID: 23118898] 
[24] 
Srinivasan, E.; Rajasekaran, R. Cysteine to serine conversion at 111th position renders the disaggregation and retains the stabilization of detrimental sod1 a4v mutant against amyotrophic lateral sclerosis in human-a discrete molecular dynamics study. Cell Biochem. Biophys.,  2018, 76(1-2), 231-241.
[http://dx.doi.org/10.1007/s12013-017-0830-5] [PMID: 28952073] 
[25] 
R R. Rational design of linear tripeptides against the aggregation of human mutant SOD1 protein causing amyotrophic lateral sclerosis. J. Neurol. Sci.,  2019, 405, 15.
[http://dx.doi.org/10.1016/j.jns.2019.116425] 
[26] 
Bedlack, R.S.; Joyce, N.; Carter, G.T.; Paganoni, S.; Karam, C. Complementary and Alternative therapies in amyotrophic lateral sclerosis. Neurol. Clin.,  2015, 33(4), 909-936.
[http://dx.doi.org/10.1016/j.ncl.2015.07.008] [PMID: 26515629] 
[27] 
Barqawi, A.; Gamito, E.; O’Donnell, C.; Crawford, E.D. Herbal and vitamin supplement use in a prostate cancer screening population. Urology,  2004, 63(2), 288-292.
[http://dx.doi.org/10.1016/j.urology.2003.09.019] [PMID: 14972473] 
[28] 
Carrera-Juliá, S.; Moreno, M.L.; Barrios, C.; de la Rubia Ortí, J.E.; Drehmer, E. Antioxidant alternatives in the treatment of amyotrophic lateral sclerosis: A comprehensive review. Front. Physiol.,  2020, 11, 63.
[http://dx.doi.org/10.3389/fphys.2020.00063] [PMID: 32116773] 
[29] 
 RCSB PDB. 1HL5: The Structure of Holo Type Human Cu, Zn Superoxide Dismutase 2020. Available from: https://www.rcsb.org/struc-ture/1hl5
[30] 
 RCSB PDB. 1UXM: A4V mutant of human SOD1 2021. Available from: https://www.rcsb.org/structure/1UXM
[31] 
 RCSB PDB. 4A7V: Structure of human I113T SOD1 mutant complexed with dopamine in the p21 space group. 2021. Available from: https://www.rcsb.org/structure/4A7V
[32] 
Strange, R.W.; Antonyuk, S.; Hough, M.A.; Doucette, P.A.; Rodriguez, J.A.; Hart, P.J.; Hayward, L.J.; Valentine, J.S.; Hasnain, S.S. The structure of holo and metal-deficient wild-type human Cu, Zn superoxide dismutase and its relevance to familial amyotrophic lateral scle-rosis. J. Mol. Biol.,  2003, 328(4), 877-891.
[http://dx.doi.org/10.1016/S0022-2836(03)00355-3] [PMID: 12729761] 
[33] 
Berman, H.M.; Battistuz, T.; Bhat, T.N.; Bluhm, W.F.; Bourne, P.E.; Burkhardt, K.; Feng, Z.; Gilliland, G.L.; Iype, L.; Jain, S.; Fagan, P.; Marvin, J.; Padilla, D.; Ravichandran, V.; Schneider, B.; Thanki, N.; Weissig, H.; Westbrook, J.D.; Zardecki, C. The protein
data bank. Acta Crystallogr. D Biol. Crystallogr.,  2002, 58(Pt 6 No 1), 899-907.
[http://dx.doi.org/10.1107/S0907444902003451] [PMID: 12037327] 
[34] 
Irwin, J.J.; Shoichet, B.K. ZINC-A free database of commercially available compounds for virtual screening. J. Chem. Inf. Model.,  2005, 45(1), 177-182. Available from: http://chembank.med.harvard.edu
[35] 
Ntie-Kang, F.; Zofou, D.; Babiaka, S.B.; Meudom, R.; Scharfe, M.; Lifongo, L.L.; Mbah, J.A.; Mbaze, L.M.; Sippl, W.; Efange, S.M. Af-roDb: A select highly potent and diverse natural product library from African medicinal plants. PLoS One,  2013, 8(10), e78085.
[http://dx.doi.org/10.1371/journal.pone.0078085] [PMID: 24205103] 
[36] 
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Methods Mol. Biol.,  2015, 1263, 243-250.
[http://dx.doi.org/10.1007/978-1-4939-2269-7_19] [PMID: 25618350] 
[37] 
Forli, S.; Huey, R.; Pique, M.E.; Sanner, M.F.; Goodsell, D.S.; Olson, A.J. Computational protein-ligand docking and virtual drug screening with the autodock suite. Nat. Protoc.,  2016, 11(5), 905-919.
[http://dx.doi.org/10.1038/nprot.2016.051] [PMID: 27077332] 
[38] 
Morris, G.M.; Lim-Wilby, M. Molecular docking. Methods Mol. Biol.,  2008, 443, 365-382.
[http://dx.doi.org/10.1007/978-1-59745-177-2_19] [PMID: 18446297] 
[39] 
Morris, GM; Goodsell, DS; Halliday, RS Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem, 19,  19, pp. 1639-1662.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B] 
[40] 
Salentin, S.; Schreiber, S.; Haupt, V.J.; Adasme, M.F.; Schroeder, M. PLIP: Fully automated protein-ligand interaction profiler. Nucleic Acids Res.,  2015, 43(W1), W443-7.
[http://dx.doi.org/10.1093/nar/gkv315] [PMID: 25873628] 
[41] 
 Drug Likeness Tool. DruLiTo 1 2020. Available from: http://www.niper.gov.in/pi_dev_tools/DruLiToWeb/DruLiTo_index.html
[42] 
Bowers, K.J.; Chow, D.E.; Xu, H. Scalable algorithms for molecular dynamics simulations on commodity clusters. SC ’06: Proceedings of the 2006 ACM/IEEE Conference on Supercomputing,  2007, pp. 43-43.
[43] 
Van Der Spoel, D.; Lindahl, E.; Hess, B.; Groenhof, G.; Mark, A.E.; Berendsen, H.J. GROMACS: Fast, flexible, and free. J. Comput. Chem.,  2005, 26(16), 1701-1718.
[http://dx.doi.org/10.1002/jcc.20291] [PMID: 16211538] 
[44] 
Schüttelkopf, A.W.; van Aalten, D.M.F. PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr.,  2004, 60(Pt 8), 1355-1363.
[http://dx.doi.org/10.1107/S0907444904011679] [PMID: 15272157] 
[45] 
Jorgensen, W.L.; Maxwell, D.S.; Tirado-Rives, J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J. Am. Chem. Soc.,  1996, 118, 11225-11236.
[http://dx.doi.org/10.1021/ja9621760] 
[46] 
Hirshman, S.P.; Whitson, J.C. Steepest-descent moment method for three-dimensional magnetohydrodynamic equilibria. Phys. Fluids,  1983, 26, 3553-3568.
[http://dx.doi.org/10.1063/1.864116] 
[47] 
Hess, B.; Bekker, H.; Berendsen, H.J.C. LINCS: A linear constraint solver for molecular simulations. J. Comput. Chem.,  1997, 18, 1463-1472.
[http://dx.doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463:AID-JCC4>3.0.CO;2-H] 

Rights & Permissions Print Cite

Article Metrics

29

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1570180819666211228093736	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

Screening of Natural Compounds Against SOD1 as a Therapeutic Target for Amyotrophic Lateral Sclerosis

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles