THEORETICAL STUDY OF THE POTENTIAL ANTI-CHAGASIC PHARMACOLOGICAL TOOL MACHILIN G: A STUDY OF MOLECULAR DOCKING
Keywords:Cruzain, Docking Molecular, Frontier Orbitals, Glyceraldehyde-3-Phosphate Dehydrogenas, Tripanothione Reductase
Chagas disease caused by Trypanosoma cruzi, which affects thousands of people around the world. In recent years, research aimed at the discovery of new drugs has started to seek specific macromolecular targets for the disease. In this context, enzymes are therapeutic targets of great interest, since they play a fundamental role in many diseases. In this context, the present work aimed to characterize the Machilin G molecule conformationally and evaluate its interactions in the main therapeutic targets involved in the replication of T. cruzi. To understand the inhibitory mechanism of Machilin G on the evolutionary forms of T. cruzi, the molecule it was conformationally characterized, until reaching thermodynamic stability, and then it was submitted to molecule docking routines, having as protein targets the Cruzain enzymes, Tripanothione reductase and glyceraldehyde-3-phosphate dehydrogenase (TcGAPDH). Machilin G had its structure optimized using semi-empirical quantum calculations, through this technique it was possible to generate the thermodynamically more stable conformation. Through the method of analysis of the computer simulations of molecular anchoring, it was demonstrated that the ligand Machilin G was coupled to the active site of the enzyme TcGAPDH, at distances close to the chalepin. In relation to Cruzain, it is possible to highlight that the ligand Machilin G does not interact with the amino acids of the active site of the enzyme, being at a considerable distance in relation to the ligand KB2. Regarding the enzyme Trypanothione reductase, the ligand Machilin G had few interactions with the amino acids of the active site. The intermolecular interactions found for the complex formed and the values obtained at a distance from the enzyme residues indicate that Machilin G has potential application as a new inhibitor of the enzyme Trypanosoma cruzi TcGAPDH. The present work being a fundamental step for the understanding of Machilin G mechanism of action in view of the evolutionary forms of the t-cruzi parasite.
N. Grandisin et al., “Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G,” no. Cl, 2016.
T. B. Cassamale, E. C. Costa, D. B. Carvalho, and N. S. Cassemiro, “Tatiana B. Cassamale,” vol. 27, no. 7, pp. 1217–1228, 2016.
G. E. Miana, S. R. Ribone, D. M. A. Vera, S. Manuel, M. R. Mazzieri, and M. A. Quevedo, “European Journal of Medicinal Chemistry Design , synthesis and molecular docking studies of novel N -arylsulfonyl-benzimidazoles with anti Trypanosoma cruzi activity,” vol. 165, pp. 1–10, 2019.
“Universidade federal da bahia faculdade de medicina fundação oswaldo cruz,” 2017.
M. M. Marinho et al., “Molecular Fractionation With Conjugate Caps Study Of The Interaction Of The Anacardic Acid With The Active Site Of Trypanosoma Cruzi Gapdh Enzyme : A Quantum Investigation,” Asian J Pharm Clin Res, vol. 12, no. 12, 2019.
F. F. Ribeiro, F. J. B. M. Junior, M. S. da Silva, M. T. ulliu. Scotti, and L. Scotti, “Computational and Investigative Study of Flavonoids Active Against Typanosoma cruzi and Leishmania spp,” Nat. Prod. Commun., 2015.
T. B. Cassamale et al., “Synthesis and Antitrypanosomastid Activity of 1,4-Diaryl-1,2,3-triazole Analogues of Neolignans Veraguensin, Grandisin and Machilin G,” J. Braz. Chem. Soc., 2016.
A. R. das Neves et al., “Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania (Leishmania) amazonensis: A structure–activity relationship comparative study with triazole-neolignan-based compounds,” Chem. Biol. Drug Des., 2019.
O. S. Trefzger et al., “Design, synthesis and antitrypanosomatid activities of 3,5-diaryl-isoxazole analogues based on neolignans veraguensin, grandisin and machilin G,” Chem. Biol. Drug Des., 2019.
E. J. Braga, B. T. Corpe, M. M. Marinho, and E. S. Marinho, “Molecular electrostatic potential surface, HOMO–LUMO, and computational analysis of synthetic drug Rilpivirine,” Int. J. Sci. Eng. Res., vol. 7, no. 7, pp. 315–319, 2016.
M. Reges, M. M. Marinho, and E. S. Marinho, “Semi-Empirical Study of the Drug Riociguat , an Important Drug for Oral Treatment against Chronic Thromboembolic Pulmonary Hypertension,” Int. J. Sci. Eng. Sci., vol. 1, no. 1, pp. 13–17, 2017.
E. S. Marinho and M. M. Marinho, “A DFT study of synthetic drug topiroxostat: MEP, HOMO, LUMO,” Int. J. Sci. Eng. Res., vol. 7, no. July, pp. 1264–1270, 2016.
J. Silva, A. R. Lima, L. L. Bezerra, M. M. Marinho, and E. S. Marinho, “Bixinoids potentially active against dengue virus: a molecular docking study,” JInternational J. Sci. Eng. Res., vol. 8, no. 4, pp. 882–887, 2017.
A. R. Lima, J. Silva, L. L. Bezerra, M. M. Marinho, and E. S. Marinho, “Molecular docking of potential curcuminoids inhibitors of the NS1 protein of dengue virus,” Int. J. Sci. Eng. Res., vol. 8, no. 4, 2017.
E. S. M. G. A. Araújo, E. P. Silva, E. P. Sanabio, J. A. Pinheiro, R.R. Castro, R.R. Castro, M.M. Marinho, F. K. S.Lima, “Characterization in Silico of the Structural Parameters of the Antifungal Agent Ketoconazole,” Sci. Signpost Publ., 2016.
M. Reges, M. M. Marinho, and E. S. Marinho, “In Silico Characterization of Hypoglycemic Agent Phenformin Using Classical Force Field MMFF94,” Int. J. Recent Res. Rev., vol. XI, no. 2, pp. 36–43, 2018.
J. Silva, A. R. Lima, L. L. Bezerra, M. M. Marinho, and E. S. Marinho, “Molecular coupling study between the potential inhibitor of dengue fever, Annatto and Protein E (DENV-4),” Int. J. Sci. Eng. Res. Vol., vol. 8, no. 7, pp. 815–821, 2017.
M. M. Marinho, R. R. Castro, and E. S. Marinho, “Utilização Do Método Semi-Empírico Pm7 Para Caracterização Do Fármaco Atalureno : Homo ,Lumo, Mesp,” Rev. Expressão Católica, vol. 1, no. 1, pp. 177–184, 2016.
Protein Data Bank, “RCSB PDB: Homepage,” RCSB PDB, 2019. .
S. Kim et al., “PubChem 2019 update: Improved access to chemical data,” Nucleic Acids Res., 2019.
J. Mancuso and R. J. McEachern, “Applications of the PM3 semi-empirical method to the study of triethylenediamine,” J. Mol. Graph. Model., 1997.
S. S. Carneiro, M. M. Marinho, and E. S. Marinho, “Electronic / Structural Characterization of Antiparkinsonian Drug Istradefylline : A Semi-Empirical Study,” Int. J. Recent Res. Rev., vol. X, no. 4, pp. 9–14, 2017.
V. M. De Oliveira, M. M. Marinho, and E. S. Marinho, “Semi-Empirical Quantum Characterization of the Drug Selexipag : HOMO and LUMO and Reactivity Descriptors,” Int. J. Recent Res. Rev., vol. XII, no. 2, pp. 15–20, 2019.
A. R. Lima, E. M. Marinho, J. Silva, M. M. Marinho, and E. S. Marinho, “Estudo In Silico Do Flavonoide Antitrombótico Ternatina , Presente Nos Capítulos Florais De In Silico Study Of Flavonoid Antithrombotic Ternatin Present In The Flowers Chapters Of Egletes Viscosa Less ‘ Macela -Da- Terra ,’” Rev. Expressão Católica Saúde, vol. 2, no. 1, 2017.
K. Brak et al., “Nonpeptidic tetrafluorophenoxymethyl ketone Cruzain inhibitors as promising new leads for chagas disease chemotherapy,” J. Med. Chem., 2010.
F. Pavão et al., “Structure of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase complexed with chalepin, a natural product inhibitor, at 1.95 AÅ resolution,” FEBS Lett., 2002.
A. Saravanamuthu, T. J. Vickers, C. S. Bond, M. R. Peterson, W. N. Hunter, and A. H. Fairlamb, “Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: A template for drug design,” J. Biol. Chem., 2004.
F. N. M. Lucio, J. E. da Silva, E. M. Marinho, F. R. D. S. Mendes, M. M. Marinho, and E. S. Marinho, “Methylcytisine Alcaloid Potentially Active Against Dengue Virus : A Molecular Docking Study And Electronic Structural Characterization,” Int. J. Res. -GRANTHAALAYAH, vol. 8, no. January, pp. 221–236, 2020.
A. K. Agrahari and C. George Priya Doss, “A Computational Approach to Identify a Potential Alternative Drug With Its Positive Impact Toward PMP22,” J. Cell. Biochem., 2017.
R. Huey, G. M. Morris, and S. Forli, “Using autodock 4 and autodock vina with autodocktools : a tutorial,” 2012.
D. S. BIOVIA et al., “Dassault Systèmes BIOVIA, Discovery Studio Visualizer, v.17.2, San Diego: Dassault Systèmes, 2016. ,” J. Chem. Phys., 2000.
E. F. Pettersen et al., “UCSF Chimera - A visualization system for exploratory research and analysis,” J. Comput. Chem., vol. 25, no. 13, pp. 1605–1612, 2004.
A. Arroio, K. M. Honório, and A. B. F. Da Silva, “Propriedades químico-quânticas empregadas em estudos das relações estrutura-atividade,” Quim. Nova, vol. 33, no. 3, pp. 694–699, 2010.
B. Nagy and F. Jensen, “Basis Sets in Quantum Chemistry,” 2017.
D. Lopes et al., “Characterization of the natural pesticide 6-desoxyclitoriacetal: a quantum study,” Int. J. Sci. Eng. Res., 2019.
L. Paes, W. L. Santos, M. M. Marinho, and E. S. Marinho, “Estudo Dft Do Alcaloide Dicentrina: Gap, Homo, Lumo, Mesp E Mulliken,” JOIN, no. 1, 2017.
T. Koopmans, “Über die Zuordnung von Wellenfunktionen und Eigenwerten zu den Einzelnen Elektronen Eines Atoms,” Physica, 1934.
F. Jensen, “Atomic orbital basis sets,” Wiley Interdisciplinary Reviews: Computational Molecular Science. 2013.
F. Jensen, “The optimum contraction of basis sets for calculating spin-spin coupling constants,” Theor. Chem. Acc., 2010.
“Cargas Atômicas em Moléculas,” Quim. Nova, 1996.
N. Prabavathi, A. Nilufer, and V. Krishnakumar, “Molecular structure, vibrational, UV, NMR, hyperpolarizability, NBO and HOMO-LUMO analysis of Pteridine2,4-dione,” Spectrochim. Acta - Part A Mol. Biomol. Spectrosc., 2012.
P. T. Okoli et al., “In Silico Study of Phytochemical Chlorogenic Acid : A Semi- Empirical Quantum Study and Adme,” Int. J. Recent Res. Rev., vol. 52, no. 4, pp. 345–357, 2019.
Kotz, Chemistry & Chemical Reactivity. 2014.
C. Henrique et al., “Characterization of the natural insecticide methylcytisine: An in silico study using classic force field,” Int. J. Recent Res. Rev., vol. XII, no. 2, pp. 15–20, 2019.
D. Lopes et al., “In Silico Studies Of Sophoraflavanone G: Quantum Characterization And Admet,” Int. J. Res. - GRANTHAALAYAH, vol. 7, no. November, pp. 160–179, 2019.
R. B. de A. E. J. Barreiro, C. R. Rodrigues, M. G. Albuquerque, C. M. R. de Sant’anna, “Molecular Modeling: A Tool for the Rational Planning of Drugs in Medicinal Chemistry,” New Chem., vol. 20, p. 1, 1997.
E. J. Barreiro, C. Alberto, and M. Fraga, Química medicinal: as bases moleculares da ação dos fármacos. .
A. R. Lima and E. S. Marinho, “Alicina uma potencial aliada contra a Chikungunya ( CHIKV ): um estudo de docking molecular,” An. do XXIII Encontro Iniciac. a Pesqui. -UNIFOR, vol. 3, 2017.
J. C. Kotz, P. M. Treichel, and J. R. Townsend, Chemistry and Chemical Reactivity. 2012.
D. Yusuf, A. M. Davis, G. J. Kleywegt, and S. Schmitt, “An alternative method for the evaluation of docking performance: RSR vs RMSD,” J. Chem. Inf. Model., 2008.
R. A. Costa et al., “CHEMISTRY Studies of NMR , molecular docking , and molecular dynamics simulation of new promising inhibitors of Cruzaine from the parasite Trypanosoma cruzi,” Med. Chem. Res., pp. 246–259, 2019.
A. A. De Marchi, S. Castilho, P. Gustavo, B. Nascimento, C. Archanjo, and D. Ponte, “New 3-piperonylcoumarins as inhibitors of glycosomal glyceraldehyde-3-phosphate dehydrogenase ( gGAPDH ) from Trypanosoma cruzi,” vol. 12, pp. 4823–4833, 2004.
A. Saravanamuthu et al., “Enzyme Catalysis and Regulation : Two Interacting Binding Sites for Quinacrine Derivatives in the Active Site of Trypanothione Reductase : A TEMPLATE FOR DRUG DESIGN Two Interacting Binding Sites for Quinacrine Derivatives in the Active Site of Trypanothione Reductase,” 2004.
V. Screening, T. Reductase, and N. P. Database, “Artigo Triagem Virtual Aplicada na Busca de Inibidores da Tripanotiona Redutase de Trypanosoma cruzi Utilizando a Base de Dados de Produtos Naturais do Semiárido Baiano ( NatProDB ) Virtual Screening applied to search of inhibitors of Trypanosoma cruzi Trypanothione Reductase employing the Natural Products Database from Bahia state ( NatProDB ) Revista Virtual de Química Triagem Virtual Aplicada na Busca de Inibidores da Tripanotiona Redutase de Trypanosoma cruzi Utilizando a Base de Dados de Produtos Naturais do Semiárido Baiano ( NatProDB ) Vinícius G . da Paixão ,* Samuel S . R . Pita,” vol. XX, no. Xx, 2016.
S. S. R, S. S. R. Pita, and P. G. Pascutti, “Artigo Alvos Terapêuticos na Doença de Chagas : a Tripanotiona Redutase como Foco Therapeutic T argets in Chagas ’ Disease : a Focus on Trypanothione Reductase Resumo Alvos Terapêuticos na Doença de Chagas : a Tripanotiona Redutase como Foco 1 . Panorama Global das Doenças,” vol. 3, no. 4, pp. 307–324, 2011.
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