Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Research Article

Modeling Molecular Study between SDO1/Inhibitors: Search of New Treatments for Amyotrophic Lateral Sclerosis

Author(s): Daiana Teixeira Mancini*, Isabela Aparecida Militani, Alexandre Alves de Castro, Letícia Cristina Assis and Teodorico de Castro Ramalho

Volume 21, Issue 10, 2024

Published on: 27 April, 2024

Page: [1707 - 1715] Pages: 9

DOI: 10.2174/1570180820666230627124449

Price: $65

Abstract

Background: The Amyotrophic lateral sclerosis (ALS) is a degenerative and most frequent motor neuron disease characterized by the progressive impairment of upper and lower motor neurons. The treatment of the disease is still palliative and limited to the use of only two drugs, riluzole and edaravone, which only prolong survival by a few months. Taking into account the low number of therapy available for this disease, identification of novel therapeutic strategies for ALS is urgently needed. The superoxide dismutase 1 (SOD1) was the first gene in which mutations were found to be causative for the neurodegenerative disease and has been used as a promising target for the ALS treatment.

Methods: In this work we used powerful computational tools (in silico method) such as Ligand-based Virtual Screening (SBVS), docking and molecular dynamics techniques to collaborate with the discovery of new candidates for more potent drugs to be used in the ALS disease treatment.

Results: Compound 1 shows good stability in the active site of the SOD1 enzyme, with an intermolecular interaction energy of -154.80 kcal/mol. In addition, the presence of some amino acids such as Glu24, Glu21, Pro28, Lys23 and Lys30 is important for to maintain stability of this compound inside SOD1.

Conclusion: This study was essential due to a low number of therapy available for this disease until the moment. With this study, it was possible to observe that Compound 1 is the most promising for the design of SOD1 mutant enzyme potential inhibitors. However, experimental tests in the SOD1 mutant to validate the inhibitory effect of Compound 1 will be required.

« Previous Next »
[1]
Hu, Y.; Yang, H.; Hou, C.; Chen, W.; Zhang, H.; Ying, Z.; Hu, Y.; Sun, Y.; Qu, Y.; Feychting, M.; Valdimarsdottir, U.; Song, H.; Fang, F. COVID-19 related outcomes among individuals with neurodegenerative diseases: a cohort analysis in the UK biobank. BMC Neurol., 2022, 22(1), 15.
[http://dx.doi.org/10.1186/s12883-021-02536-7] [PMID: 34996388]
[2]
Ramalho, T.C.; de Castro, A.A.; Tavares, T.S.; Silva, M.C.; Silva, D.R.; Cesar, P.H.; Santos, L.A.; da Cunha, E.F.F.; Nepovimova, E.; Kuca, K. In-sights into the pharmaceuticals and mechanisms of neurological orphan diseases: Current Status and future expectations. Prog. Neurobiol., 2018, 169, 135-157.
[http://dx.doi.org/10.1016/j.pneurobio.2018.06.011] [PMID: 29981392]
[3]
Wainstocka, D.; Katzb, A. Advancing rare disease policy in Latin America: A call to action. Lancet Reg. Health Am., 2023, 18, 100434.
[http://dx.doi.org/10.1016/j.lana.2023.100434] [PMID: 36844013]
[4]
Hardiman, O.; Al-Chalabi, A.; Chio, A.; Corr, E.M.; Logroscino, G.; Robberecht, W.; Shaw, P.J.; Simmons, Z.; van den Berg, L.H. Amyotrophic lateral sclerosis. Nat. Rev. Dis. Primers, 2017, 3(1), 17071.
[http://dx.doi.org/10.1038/nrdp.2017.71] [PMID: 28980624]
[5]
Mead, R.J.; Shan, N.; Reiser, H.J.; Marshall, F.; Shaw, P.J. Amyotrophic lateral sclerosis: A neurodegenerative disorder poised for successful therapeutic translation. Nat. Rev. Drug Discov., 2023, 22(3), 185-212.
[http://dx.doi.org/10.1038/s41573-022-00612-2] [PMID: 36543887]
[6]
Huang, H.J.; Chang, T.T.; Chen, H.Y.; Chen, C.Y.C. Finding inhibitors of mutant superoxide dismutase-1 for amyotrophic lateral sclerosis therapy from traditional chinese medicine. Evid. Based Complement. Alternat. Med., 2014, 2014, 1-12.
[http://dx.doi.org/10.1155/2014/156276] [PMID: 24963318]
[7]
Xu, X.; Shen, D.; Gao, Y.; Zhou, Q.; Ni, Y.; Meng, H.; Shi, H.; Le, W.; Chen, S.; Chen, S. A perspective on therapies for amyotrophic lateral sclerosis: Can disease progression be curbed? Transl. Neurodegener., 2021, 10(1), 29.
[http://dx.doi.org/10.1186/s40035-021-00250-5] [PMID: 34372914]
[8]
Jaiswal, M.K. Riluzole and edaravone: A tale of two amyotrophic lateral sclerosis drugs. Med. Res. Rev., 2019, 39(2), 733-748.
[http://dx.doi.org/10.1002/med.21528] [PMID: 30101496]
[9]
Kawano, C.; Isozaki, Y.; Nakagawa, A.; Hirayama, T.; Nishiyama, K.; Kuroyama, M. Liver injury risk factors in amyotrophic lateral sclerosis patients treated with riluzole. Yakugaku Zasshi, 2020, 140(7), 923-928.
[http://dx.doi.org/10.1248/yakushi.20-00015] [PMID: 32612057]
[10]
Riluzole. 2021. Available from: https://www.drugs.com/mtm/riluzole.html
[11]
Brooks, B.R.; Jorgenson, J.A.; Newhouse, B.J.; Shefner, J.M.; Agnese, W. Edaravone in the treatment of amyotrophic lateral sclerosis: efficacy and access to therapy-A roundtable discussion. Am. J. Manag. Care, 2018, 24(9)(Suppl.), S175-S186.
[PMID: 29693363]
[12]
Liu, X.; Zhang, J.; Li, J.; Song, C.; Shi, Y. Pharmacological inhibition of ALCAT1 mitigates amyotrophic lateral sclerosis by attenuating SOD1 protein aggregation. Mol. Metab., 2022, 63, 101536.
[http://dx.doi.org/10.1016/j.molmet.2022.101536] [PMID: 35772643]
[13]
Rosa, A.C.; Corsi, D.; Cavi, N.; Bruni, N.; Dosio, F. Superoxide dismutase administration: A review of proposed human uses. Molecules, 2021, 26(7), 1844.
[http://dx.doi.org/10.3390/molecules26071844] [PMID: 33805942]
[14]
da Cunha, E.F.F.; Mancini, D.T.; Ramalho, T.C. Molecular modeling of the Toxoplasma gondii adenosine kinase inhibitors. Med. Chem. Res., 2012, 21(5), 590-600.
[http://dx.doi.org/10.1007/s00044-011-9554-z]
[15]
Mancini, D.T.; Matos, K.S.; da Cunha, E.F.F.; Assis, T.M.; Guimarães, A.P.; França, T.C.C.; Ramalho, T.C. Molecular modeling studies on nucleoside hydrolase from the biological warfare agent Brucella suis. J. Biomol. Struct. Dyn., 2012, 30(1), 125-136.
[http://dx.doi.org/10.1080/07391102.2012.674293] [PMID: 22571438]
[16]
Kuca, K.; Musilek, K.; Jun, D.; Zdarova-Karasova, J.; Nepovimova, E.; Soukup, O.; Hrabinova, M.; Mikler, J.; Franca, T.C.C.; Da Cunha, E.F.F.; De Castro, A.A.; Valis, M.; Ramalho, T.C. A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase. BMC Pharmacol. Toxicol., 2018, 19(1), 8.
[http://dx.doi.org/10.1186/s40360-018-0196-3] [PMID: 29467029]
[17]
Woo, T.G.; Yoon, M.H.; Kang, S.; Park, S.; Cho, J.H.; Hwang, Y.J.; Ahn, J.; Jang, H.; Shin, Y.J.; Jung, E.M.; Ha, N.C.; Kim, B.H.; Kwon, Y.; Park, B.J. Novel chemical inhibitor against SOD1 misfolding and aggregation protects neuron-loss and ameliorates disease symptoms in ALS mouse model. Commun. Biol., 2021, 4(1), 1397.
[http://dx.doi.org/10.1038/s42003-021-02862-z] [PMID: 34912047]
[18]
Wright, G.S.A.; Antonyuk, S.V.; Kershaw, N.M.; Strange, R.W.; Hasnain, S.S. Structure of human I113T SOD1 mutant complexed with dopamine in the p21 space group. Nat. Commun., 2013, 4, 1758.
[http://dx.doi.org/10.1038/ncomms2750] [PMID: 23612299]
[19]
Kuntz, I.D.; Blaney, J.M.; Oatley, S.J.; Langridge, R.; Ferrin, T.E. A geometric approach to macromolecule-ligand interactions. J. Mol. Biol., 1982, 161(2), 269-288.
[http://dx.doi.org/10.1016/0022-2836(82)90153-X] [PMID: 7154081]
[20]
Koes, D.R.; Camacho, C.J. ZINCPharmer: Pharmacophore search of the ZINC database. Nucleic Acids Res, 2012, 40(Web Server issue), W409-W414.
[http://dx.doi.org/10.1093/nar/gks378] [PMID: 22553363]
[21]
Thomsen, R.; Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking. J. Med. Chem., 2006, 49(11), 3315-3321.
[http://dx.doi.org/10.1021/jm051197e] [PMID: 16722650]
[22]
Hevener, K.E.; Zhao, W.; Ball, D.M.; Babaoglu, K.; Qi, J.; White, S.W.; Lee, R.E. Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J. Chem. Inf. Model., 2009, 49(2), 444-460.
[http://dx.doi.org/10.1021/ci800293n] [PMID: 19434845]
[23]
Mysinger, M.M.; Carchia, M.; Irwin, J.J.; Shoichet, B.K. Directory of useful decoys, enhanced (DUD-E): Better ligands and decoys for better bench-marking. J. Med. Chem., 2012, 55(14), 6582-6594.
[http://dx.doi.org/10.1021/jm300687e] [PMID: 22716043]
[24]
Páll, S.; Abraham, M.J.; Kutzner, C.; Hess, B.; Lindahl, E. Tackling exascale software challenges in molecular dynamics simulations with GROMACS; Springer: Cham, 2015, p. 8759.
[http://dx.doi.org/10.1007/978-3-319-15976-8_1]
[25]
Scott, W.R.P.; Hünenberger, P.H.; Tironi, I.G.; Mark, A.E.; Billeter, S.R.; Fennen, J.; Torda, A.E.; Huber, T.; Krüger, P.; van Gunsteren, W.F. The GROMOS biomolecular simulation program package. J. Phys. Chem. A, 1999, 103(19), 3596-3607.
[http://dx.doi.org/10.1021/jp984217f]
[26]
Parrinello, M.; Rahman, A. Polymorphic transitions in single crystals: A new molecular dynamics method. J. Appl. Phys., 1981, 52(12), 7182-7190.
[http://dx.doi.org/10.1063/1.328693]
[27]
Darden, T.; York, D.; Pedersen, L. Particle mesh Ewald: An N ⋅log(N) method for Ewald sums in large systems. J. Chem. Phys., 1993, 98(12), 10089-10092.
[http://dx.doi.org/10.1063/1.464397]
[28]
Humphrey, W.; Dalke, A.; Schulten, K. VMD: Visual molecular dynamics. J. Mol. Graph., 1996, 14(1), 33-38. 27-28.
[http://dx.doi.org/10.1016/0263-7855(96)00018-5] [PMID: 8744570 ]
[29]
Guimarães, A.P.; Oliveira, A.A.; da Cunha, E.F.F.; Ramalho, T.C.; França, T.C.C. Design of new chemotherapeutics against the deadly anthrax disease. Docking and molecular dynamics studies of inhibitors containing pyrrolidine and riboamidrazone rings on nucleoside hydrolase from Bacillus anthracis. J. Biomol. Struct. Dyn., 2011, 28(4), 455-469.
[http://dx.doi.org/10.1080/07391102.2011.10508588] [PMID: 21142217]
[30]
Braga, L.S.; Silva, É.F.; Mancini, D.T.; da Rocha, E.P.; da Cunha, E.F.F.; Ramalho, T.C. Detection of chemical weapon agents using spectroscopic probes: A computational study. J. Chem., 2020, 2020, 1-11.
[http://dx.doi.org/10.1155/2020/1312403]
[31]
de Castro, A.A.; Soares, F.V.; Pereira, A.F.; Silva, T.C.; Silva, D.R.; Mancini, D.T.; Caetano, M.S.; da Cunha, E.F.F.; Ramalho, T.C. Asymmetric bio-degradation of the nerve agents Sarin and VX by human dUTPase: chemometrics, molecular docking and hybrid QM/MM calculations. J. Biomol. Struct. Dyn., 2019, 37(8), 2154-2164.
[http://dx.doi.org/10.1080/07391102.2018.1478751] [PMID: 30044197]
[32]
Melo, F. Area under the ROC Curve BT - Encyclopedia of Systems Biology.Springer New York, New York; Dubitzky, W.; Wolkenhauer, O.; Cho, K-H; Yokota, H., Ed.; NY, 2013, pp. 38-39.
[33]
Malik, R.; Corrales, C.; Linsenmeier, M.; Alalami, H.; Sepanj, N.; Bitan, G. Examination of SOD1 aggregation modulators and their effect on SOD1 enzymatic activity as a proxy for potential toxicity. FASEB J., 2020, 34(9), 11957-11969.
[http://dx.doi.org/10.1096/fj.202000948R] [PMID: 32701214]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy