Abstract
Introduction: Charcot Marie Tooth Disease-2 is a debilitating neurogenetic disorder that adversely affects peripheral neurons by disrupting mitochondrial activity. Mutated mitofusin-2 (MFN) is the main culprit behind disruptive mitochondrial function and is considered a therapeutic target in identifying drugs for treating this disease. This disease has no therapeutic medication except for supportive care.
Objective: The objective of the current study is to evaluate high-affinity medicinal compounds for mutated MFN-2 and describe their absorption, distribution, metabolism, excretion, and toxic attributes (ADMET).
Methods: For ADMET properties, 2,219 medicinal compounds were analyzed with AutoDock Vina using PyRX 0.9 software against MFN-2, SwissADME, and GUSAR.
Results: Results from screening studies revealed that three compounds (Liriodenine, Pinocembrin, and Vestitol) show an affinity for amino acids present in the predicted active interface of the MFN-2 protein. Moreover, these compounds render low toxicity and efficient ADME qualities, combined with bloodbrain barrier permeability, drug-likeness, and lead-likeness.
Conclusion: Liriodenine, pinocembrin and vestitol are therapeutic compounds for CMT-2 treatment and should be used in further in vitro studies to confirm the results of this research.
[1]
Gutmann, L.; Shy, M. Update on Charcot–Marie–Tooth disease. Curr. Opin. Neurol., 2015, 28(5), 462-467.
[http://dx.doi.org/10.1097/WCO.0000000000000237] [PMID: 26263471]
[http://dx.doi.org/10.1097/WCO.0000000000000237] [PMID: 26263471]
[2]
Barreto, L.C.L.S.; Oliveira, F.S.; Nunes, P.S.; de França Costa, I.M.P.; Garcez, C.A.; Goes, G.M.; Neves, E.L.A.; de Souza Siqueira Quintans, J.; de Souza Araújo, A.A. Epidemiologic study of Charcot-Marie-Tooth disease: A systematic review. Neuroepidemiology, 2016, 46(3), 157-165.
[http://dx.doi.org/10.1159/000443706] [PMID: 26849231]
[http://dx.doi.org/10.1159/000443706] [PMID: 26849231]
[3]
Ramchandren, S. Charcot-Marie-Tooth disease and other genetic polyneuropathies. Continuum, 2017, 23(5), 1360-1377.
[http://dx.doi.org/10.1212/CON.0000000000000529] [PMID: 28968366]
[http://dx.doi.org/10.1212/CON.0000000000000529] [PMID: 28968366]
[4]
Arnold, W.D.; Isfort, M.; Roggenbuck, J.; Hoyle, J.C. The genetics of Charcot–Marie–Tooth disease: Current trends and future implications for diagnosis and management. Appl. Clin. Genet., 2015, 8, 235-243.
[http://dx.doi.org/10.2147/TACG.S69969] [PMID: 26527893]
[http://dx.doi.org/10.2147/TACG.S69969] [PMID: 26527893]
[5]
Rossor, A.M.; Shy, M.E.; Reilly, M.M. Are we prepared for clinical trials in Charcot-Marie-Tooth disease? Brain Res., 2020, 1729, 146625.
[http://dx.doi.org/10.1016/j.brainres.2019.146625] [PMID: 31899213]
[http://dx.doi.org/10.1016/j.brainres.2019.146625] [PMID: 31899213]
[6]
Beręsewicz, M.; Charzewski, Ł.; Krzyśko, K.A.; Kochański, A.; Zabłocka, B. Molecular modelling of mitofusin 2 for a prediction for Charcot-Marie-Tooth 2A clinical severity. Sci. Rep., 2018, 8(1), 16900.
[http://dx.doi.org/10.1038/s41598-018-35133-9] [PMID: 30442897]
[http://dx.doi.org/10.1038/s41598-018-35133-9] [PMID: 30442897]
[7]
Rocha, A.G.; Franco, A.; Krezel, A.M.; Rumsey, J.M.; Alberti, J.M.; Knight, W.C.; Biris, N.; Zacharioudakis, E.; Janetka, J.W.; Baloh, R.H.; Kitsis, R.N.; Mochly-Rosen, D.; Townsend, R.R.; Gavathiotis, E.; Dorn, G.W. MFN2 agonists reverse mitochondrial defects in preclinical models of charcot-marie-tooth disease type 2A. Science, 2018, 360(6386), 336-341.
[http://dx.doi.org/10.1126/science.aao1785]
[http://dx.doi.org/10.1126/science.aao1785]
[8]
Franco, A.; Dang, X.; Walton, E.K.; Ho, J.N.; Zablocka, B.; Ly, C.; Miller, T.M.; Baloh, R.H.; Shy, M.E.; Yoo, A.S.; Dorn, G.W., II Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A. eLife, 2020, 9, e61119.
[http://dx.doi.org/10.7554/eLife.61119] [PMID: 33074106]
[http://dx.doi.org/10.7554/eLife.61119] [PMID: 33074106]
[9]
Wolf, C.; Zimmermann, R.; Thaher, O.; Bueno, D.; Wüllner, V.; Schäfer, M.K.E.; Albrecht, P.; Methner, A. The Charcot–Marie tooth disease mutation R94Q in MFN2 decreases ATP production but increases mitochondrial respiration under conditions of mild oxidative stress. Cells, 2019, 8(10), 1289.
[http://dx.doi.org/10.3390/cells8101289] [PMID: 31640251]
[http://dx.doi.org/10.3390/cells8101289] [PMID: 31640251]
[10]
Lee, J.H.; Choi, B.O. Charcot-marie-tooth disease: Seventeen causative genes. J. Clin. Neurol., 2006, 2(2), 92-106.
[http://dx.doi.org/10.3988/jcn.2006.2.2.92] [PMID: 20396492]
[http://dx.doi.org/10.3988/jcn.2006.2.2.92] [PMID: 20396492]
[11]
Choi, B.O.; Nakhro, K.; Park, H.J.; Hyun, Y.S.; Lee, J.H.; Kanwal, S.; Jung, S.C.; Chung, K.W. A cohort study of MFN2 mutations and phenotypic spectrums in Charcot-Marie-Tooth disease 2A patients. Clin. Genet., 2015, 87(6), 594-598.
[http://dx.doi.org/10.1111/cge.12432] [PMID: 24863639]
[http://dx.doi.org/10.1111/cge.12432] [PMID: 24863639]
[12]
Schrepfer, E.; Scorrano, L. Mitofusins, from mitochondria to metabolism. Mol. Cell, 2016, 61(5), 683-694.
[http://dx.doi.org/10.1016/j.molcel.2016.02.022] [PMID: 26942673]
[http://dx.doi.org/10.1016/j.molcel.2016.02.022] [PMID: 26942673]
[13]
Dorn, G.W., II Mitofusin 2 dysfunction and disease in mice and men. Front. Physiol., 2020, 11, 782.
[http://dx.doi.org/10.3389/fphys.2020.00782] [PMID: 32733278]
[http://dx.doi.org/10.3389/fphys.2020.00782] [PMID: 32733278]
[14]
Iwata, K.; Scorrano, L. Finding a new balance to cure Charcot-Marie-Tooth 2A. J. Clin. Invest., 2019, 129(4), 1533-1535.
[http://dx.doi.org/10.1172/JCI127820] [PMID: 30882369]
[http://dx.doi.org/10.1172/JCI127820] [PMID: 30882369]
[15]
Li, Y.J.; Cao, Y.L.; Feng, J.X.; Qi, Y.; Meng, S.; Yang, J.F.; Zhong, Y.T.; Kang, S.; Chen, X.; Lan, L.; Luo, L.; Yu, B.; Chen, S.; Chan, D.C.; Hu, J.; Gao, S. Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset. Nat. Commun., 2019, 10(1), 4914.
[http://dx.doi.org/10.1038/s41467-019-12912-0] [PMID: 31664033]
[http://dx.doi.org/10.1038/s41467-019-12912-0] [PMID: 31664033]
[16]
Zhou, Y.; Carmona, S.; Muhammad, A.K.M.G.; Bell, S.; Landeros, J.; Vazquez, M.; Ho, R.; Franco, A.; Lu, B.; Dorn, G.W., II; Wang, S.; Lutz, C.M.; Baloh, R.H. Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model. J. Clin. Invest., 2019, 129(4), 1756-1771.
[http://dx.doi.org/10.1172/JCI124194] [PMID: 30882371]
[http://dx.doi.org/10.1172/JCI124194] [PMID: 30882371]
[17]
Franco, A.; Kitsis, R.N.; Fleischer, J.A.; Gavathiotis, E.; Kornfeld, O.S.; Gong, G.; Biris, N.; Benz, A.; Qvit, N.; Donnelly, S.K.; Chen, Y.; Mennerick, S.; Hodgson, L.; Mochly-Rosen, D.; Dorn, G.W., II Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature, 2016, 540(7631), 74-79.
[http://dx.doi.org/10.1038/nature20156] [PMID: 27775718]
[http://dx.doi.org/10.1038/nature20156] [PMID: 27775718]
[18]
Shah, F.H.; Salman, S.; Idrees, J.; Idrees, F.; Akbar, M.Y. In silico study of thymohydroquinone interaction with blood–brain barrier disrupting proteins. Future Sci. OA, 2020, 6(10), FSO632.
[http://dx.doi.org/10.2144/fsoa-2020-0115] [PMID: 33312701]
[http://dx.doi.org/10.2144/fsoa-2020-0115] [PMID: 33312701]
[19]
Xu, D.; Zhang, Y. Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys. J., 2011, 101(10), 2525-2534.
[http://dx.doi.org/10.1016/j.bpj.2011.10.024] [PMID: 22098752]
[http://dx.doi.org/10.1016/j.bpj.2011.10.024] [PMID: 22098752]
[20]
van Aalten, D.M.F.; Bywater, R.; Findlay, J.B.C.; Hendlich, M.; Hooft, R.W.W.; Vriend, G. PRODRG, a program for generating molecular topologies and unique molecular descriptors from coordinates of small molecules. J. Comput. Aided Mol. Des., 1996, 10(3), 255-262.
[http://dx.doi.org/10.1007/BF00355047] [PMID: 8808741]
[http://dx.doi.org/10.1007/BF00355047] [PMID: 8808741]
[21]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. In: Chemical biology; Humana Press: New York, NY, 2015; pp. 243-250.
[http://dx.doi.org/10.1007/978-1-4939-2269-7_19]
[http://dx.doi.org/10.1007/978-1-4939-2269-7_19]
[22]
Trott, O.; Olson, A.J. 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.
[PMID: 19499576]
[PMID: 19499576]
[23]
Kumar, S.; Khatik, G.L.; Mittal, A. In silico molecular docking study to search new SGLT2 inhibitor based on dioxabicyclo[3.2.1] octane scaffold. Curr. Comput. Drug Des., 2020, 16(2), 145-154.
[http://dx.doi.org/10.2174/1573409914666181019165821] [PMID: 30345926]
[http://dx.doi.org/10.2174/1573409914666181019165821] [PMID: 30345926]
[24]
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(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[25]
Lagunin, A.; Zakharov, A.; Filimonov, D.; Poroikov, V. QSAR modelling of rat acute toxicity on the basis of PASS prediction. Mol. Inform., 2011, 30(2-3), 241-250.
[http://dx.doi.org/10.1002/minf.201000151] [PMID: 27466777]
[http://dx.doi.org/10.1002/minf.201000151] [PMID: 27466777]
[26]
Ivanov, S.M.; Lagunin, A.A.; Rudik, A.V.; Filimonov, D.A.; Poroikov, V.V. ADVERPred–Web service for prediction of adverse effects of drugs. J. Chem. Inf. Model., 2018, 58(1), 8-11.
[http://dx.doi.org/10.1021/acs.jcim.7b00568] [PMID: 29206457]
[http://dx.doi.org/10.1021/acs.jcim.7b00568] [PMID: 29206457]
[27]
Lagunin, A.; Rudik, A.; Druzhilovsky, D.; Filimonov, D.; Poroikov, V.; Wren, J. ROSC-Pred: Web-service for rodent organ-specific carcinogenicity prediction. Bioinformatics, 2018, 34(4), 710-712.
[http://dx.doi.org/10.1093/bioinformatics/btx678] [PMID: 29069300]
[http://dx.doi.org/10.1093/bioinformatics/btx678] [PMID: 29069300]
[28]
Poroikov, V.V.; Filimonov, D.A.; Ihlenfeldt, W.D.; Gloriozova, T.A.; Lagunin, A.A.; Borodina, Y.V.; Stepanchikova, A.V.; Nicklaus, M.C. PASS biological activity spectrum predictions in the enhanced open NCI database browser. J. Chem. Inf. Comput. Sci., 2003, 43(1), 228-236.
[http://dx.doi.org/10.1021/ci020048r] [PMID: 12546557]
[http://dx.doi.org/10.1021/ci020048r] [PMID: 12546557]
[29]
Lagunin, A.; Ivanov, S.; Rudik, A.; Filimonov, D.; Poroikov, V. DIGEP-Pred: Web service for in silico prediction of drug-induced gene expression profiles based on structural formula. Bioinformatics, 2013, 29(16), 2062-2063.
[http://dx.doi.org/10.1093/bioinformatics/btt322] [PMID: 23740741]
[http://dx.doi.org/10.1093/bioinformatics/btt322] [PMID: 23740741]
[30]
Velázquez-Libera, J.L.; Durán-Verdugo, F.; Valdés-Jiménez, A.; Núñez-Vivanco, G.; Caballero, J. LigRMSD: A web server for automatic structure matching and RMSD calculations among identical and similar compounds in protein-ligand docking. Bioinformatics, 2020, 36(9), 2912-2914.
[http://dx.doi.org/10.1093/bioinformatics/btaa018] [PMID: 31926012]
[http://dx.doi.org/10.1093/bioinformatics/btaa018] [PMID: 31926012]
[31]
Escobar-Henriques, M.; Joaquim, M. Mitofusins: Disease Gatekeepers and Hubs in Mitochondrial Quality Control by E3 Ligases. Front. Physiol., 2019, 10, 517.
[http://dx.doi.org/10.3389/fphys.2019.00517] [PMID: 31156446]
[http://dx.doi.org/10.3389/fphys.2019.00517] [PMID: 31156446]
[32]
Barbosa, R.A.; Nunes, T.L.G.M.; Nunes, T.L.G.M.; Paixão, A.O.; Neto, R.B.; Moura, S.; Albuquerque Junior, R.L.C.; Cândido, E.A.F.; Padilha, F.F.; Quintans-Júnior, L.J.; Gomes, M.Z.; Cardoso, J.C. Hydroalcoholic extract of red propolis promotes functional recovery and axon repair after sciatic nerve injury in rats. Pharm. Biol., 2016, 54(6), 993-1004.
[http://dx.doi.org/10.3109/13880209.2015.1091844] [PMID: 26511070]
[http://dx.doi.org/10.3109/13880209.2015.1091844] [PMID: 26511070]
[33]
Bota, O.; Fodor, L. The influence of drugs on peripheral nerve regeneration. Drug Metab. Rev., 2019, 51(3), 266-292.
[http://dx.doi.org/10.1080/03602532.2019.1632885] [PMID: 31203666]
[http://dx.doi.org/10.1080/03602532.2019.1632885] [PMID: 31203666]
[34]
Mohd Sairazi, N.S.; Sirajudeen, K.N.S. Natural products and their bioactive compounds: Neuroprotective potentials against neurodegenerative diseases. Evid. Based Complement. Alternat. Med., 2020, 2020, 1-30.
[http://dx.doi.org/10.1155/2020/6565396] [PMID: 32148547]
[http://dx.doi.org/10.1155/2020/6565396] [PMID: 32148547]
