Navegar

Colección

Datos Estadísticas

Artículo

Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor

Abstract:

Chagas disease or American trypanosomiasis is a parasitic disease caused by the protozoan Trypanosoma cruzi. Its squalene epoxidase (SE) is a target for drug design and development because it is a key enzyme in the biosynthetic pathway of ergosterol, which is essential for the life cycle of the parasite. Previously, we reported that some 4-arylthiazolylhydrazones derived from 1-indanones (TZHs) active against T. cruzi are able to accumulate squalene probably by SE inhibition. In this work, we performed a series of theoretical studies to verify that TZHs act as inhibitors of this enzyme. Since the crystal structure of SE is unknown for all species, we built a 3D enzyme model of T. cruzi SE by homology modeling. Based on this model, we carried out docking, molecular dynamics, and MM/PBSA calculations and the results were compared with those found for the reference inhibitor compound terbinafine (Tbf). The binding free energy values allowed the discrimination between accumulators and non-accumulators of squalene compounds, in agreement with the experimental findings. Pairwise residue free energy decomposition showed that the key amino acids involved in inhibitor binding for TZHs and Tbf were the same. Also, molecular superposition analysis between these compounds revealed high structural similarity. In addition, we proposed a pharmacophore model for T. cruzi SE inhibitors, which confirmed that TZHs and Tbf share chemical features with respect to their biochemical interaction characteristics at similar positions in 3D space. All theoretical calculations suggest that the experimentally observed squalene accumulation is produced by T. cruzi SE inhibition. © The Royal Society of Chemistry.

Registro:

Documento: Artículo
Título:Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations
Autor:Noguera, G.J.; Fabian, L.E.; Lombardo, E.; Finkielsztein, L.M.
Filiación:Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Cátedra de Química Medicinal, Junín 956, 1113, Ciudad Autónoma de Buenos Aires, Argentina
CONICET-Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA), Junín 956, 1113, Ciudad Autónoma de Buenos Aires, Argentina
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica, Pabellón II, Ciudad Universitaria, 1428, Ciudad Autónoma de Buenos Aires, Argentina
CONICET-Universidad de Buenos Aires, Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP), Avenida Córdoba 2351, 1120, Ciudad Autónoma de Buenos Aires, Argentina
Palabras clave:Crystal structure; Enzymes; Free energy; Life cycle; Molecular dynamics; Biochemical interactions; Biosynthetic pathway; Molecular simulations; Pharmacophore modeling; Protozoan Trypanosoma; Structural similarity; Superposition analysis; Theoretical calculations; Binding energy; enzyme inhibitor; hydrazone derivative; indan derivative; squalene monooxygenase; amino acid sequence; antagonists and inhibitors; chemistry; drug design; enzymology; metabolism; molecular docking; molecular dynamics; molecular model; protein conformation; thermodynamics; Trypanosoma cruzi; Amino Acid Sequence; Drug Design; Enzyme Inhibitors; Hydrazones; Indans; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Conformation; Squalene Monooxygenase; Thermodynamics; Trypanosoma cruzi
Año:2018
Volumen:16
Número:44
Página de inicio:8525
Página de fin:8536
DOI: http://dx.doi.org/10.1039/C8OB02310G
Título revista:Organic and Biomolecular Chemistry
Título revista abreviado:Org. Biomol. Chem.
ISSN:14770520
CODEN:OBCRA
CAS:squalene monooxygenase, 9029-62-3; Enzyme Inhibitors; Hydrazones; Indans; Squalene Monooxygenase
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_14770520_v16_n44_p8525_Noguera

Referencias:

  • Pecoul, B., Batista, C., Stobbaerts, E., Ribeiro, I., Vilasanjuan, R., Gascon, J., Pinazo, M.J., Hotez, P.J., (2016) PLoS Neglected Trop. Dis., 10, p. e0004343
  • http://www.who.int/chagas/; Schmunis, G.A., Yadon, Z.E., (2010) Acta Trop., 115, pp. 14-21
  • Croft, S.L., Barrett, M.P., Urbina, J.A., (2005) Trends Parasitol., 21, pp. 508-512
  • Werner, B.A., Heitmann, I.G., Jercic, M.I., Jofré, L.M., Muñoz, P.C., Noemí, I.H., San Martín, A.M., Zulantay, I.A., (2008) Rev Chilena. Infectol., 25, pp. 384-389
  • Caputto, M.E., Ciccarelli, A., Frank, F., Moglioni, A.G., Moltrasio, G.Y., Vega, D., Lombardo, E., Finkielsztein, L.M., (2012) Eur. J. Med. Chem., 55, pp. 155-163
  • Noguera, G.J., Fabian, L.E., Lombardo, E., Finkielsztein, L., (2015) Eur. J. Pharm. Sci., 78, pp. 190-197
  • De Souza, W., Rodrigues, J.C., (2009) Interdiscip. Perspect. Infect. Dis., 2009, p. 642502
  • Buckner, F.S., Griffin, J.H., Wilson, A.J., Van Voorhis, W.C., (2001) Antimicrob. Agents Chemother., 45, pp. 1210-1215
  • Ruckenstuhl, C., Lang, S., Poschenel, A., Eidenberger, A., Baral, P.K., Kohut, P., Hapala, I., Turnowsky, F., (2007) Antimicrob. Agents Chemother., 51, pp. 275-284
  • Lee, H.K., Zheng, Y.F., Xiao, X.Y., Bai, M., Sakakibara, J., Ono, T., Prestwich, G.D., (2004) Biochem. Biophys. Res. Commun., 315, pp. 1-9
  • Klobucnikova, V., Kohut, P., Leber, R., Fuchsbichler, S., Schweighofer, N., Turnowsky, F., Hapala, I., (2003) Biochem. Biophys. Res. Commun., 309, pp. 666-671
  • Leber, R., Fuchsbichler, S., Klobucnikova, V., Schweighofer, N., Pitters, E., Wohlfarter, K., Lederer, M., Turnowsky, F., (2003) Antimicrob. Agents Chemother., 47, pp. 3890-3900
  • Kumar, A., Jha, A., (2017) Anticandidal Agents, pp. 11-39. , Academic Press
  • Urbina, J.A., Concepcion, J.L., Rangel, S., Visbal, G., Lira, R., (2002) Mol. Biochem. Parasitol., 125, pp. 35-45
  • Urbina, J.A., (2002) Curr. Pharm. Des., 8, pp. 287-295
  • Nowosielski, M., Hoffmann, M., Wyrwicz, L.S., Stepniak, P., Plewczynski, D.M., Lazniewski, M., Ginalski, K., Rychlewski, L., (2011) J. Chem. Inf. Model., 51, pp. 455-462
  • Bostrom, J., Hogner, A., Schmitt, S., (2006) J. Med. Chem., 49, pp. 6716-6725
  • Vainio, M.J., Puranen, J.S., Johnson, M.S., (2009) J. Chem. Inf. Model., 49, pp. 492-502
  • Krieger, E., Nabuurs, S.B., Vriend, G., (2003) Structural Bioinformatics, pp. 509-523. , ed. P. E. Bourne and H. HelgeWeissig, Wiley, New Jersey
  • Webb, B., Sali, A., (2014) Curr. Protoc. Bioinf., 47, pp. 561-5632
  • Shen, M.Y., Sali, A., (2006) Protein Sci., 15, pp. 2507-2524
  • John, B., Sali, A., (2003) Nucleic Acids Res., 31, pp. 3982-3992
  • Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., Olson, A.J., (2009) J. Comput. Chem., 30, pp. 2785-2791
  • Trott, O., Olson, A.J., (2010) J. Comput. Chem., 31, pp. 455-461
  • Phillips, J.C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Schulten, K., (2005) J. Comput. Chem., 26, pp. 1781-1802
  • Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A., Case, D.A., (2004) J. Comput. Chem., 25, pp. 1157-1174
  • Miller, B.R., McGee, T.D., Jr., Swails, J.M., Homeyer, N., Gohlke, H., Roitberg, A.E., (2012) J. Chem. Theory Comput., 8, pp. 3314-3321
  • Rastelli, G., Del Rio, A., Degliesposti, G., Sgobba, M., (2010) J. Comput. Chem., 31, pp. 797-810
  • Wolber, G., Dornhofer, A.A., Langer, T., (2006) J. Comput. Aided Mol. Des., 20, pp. 773-788
  • Favre, B., Ryder, N.S., (1996) Antimicrob. Agents Chemother., 40, pp. 443-447
  • Sulsen, V.P., Puente, V., Papademetrio, D., Batlle, A., Martino, V.S., Frank, F.M., Lombardo, M.E., (2016) PLoS One, 11, p. e0150526
  • Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., Ferrin, T.E., (2004) J. Comput. Chem., 25, pp. 1605-1612
  • https://www.uniprot.org/; https://biophysics.cs.vt.edu/; O'Boyle, N.M., Banck, M., James, C.A., Morley, C., Vandermeersch, T., Hutchison, G.R., (2011) J. Cheminf., 3, p. 33
  • Humphrey, W., Dalke, A., Schulten, K., (1996) J. Mol. Graphics, 14, pp. 33-38

Citas:

---------- APA ----------
Noguera, G.J., Fabian, L.E., Lombardo, E. & Finkielsztein, L.M. (2018) . Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations. Organic and Biomolecular Chemistry, 16(44), 8525-8536.
http://dx.doi.org/10.1039/C8OB02310G
---------- CHICAGO ----------
Noguera, G.J., Fabian, L.E., Lombardo, E., Finkielsztein, L.M. "Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations" . Organic and Biomolecular Chemistry 16, no. 44 (2018) : 8525-8536.
http://dx.doi.org/10.1039/C8OB02310G
---------- MLA ----------
Noguera, G.J., Fabian, L.E., Lombardo, E., Finkielsztein, L.M. "Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations" . Organic and Biomolecular Chemistry, vol. 16, no. 44, 2018, pp. 8525-8536.
http://dx.doi.org/10.1039/C8OB02310G
---------- VANCOUVER ----------
Noguera, G.J., Fabian, L.E., Lombardo, E., Finkielsztein, L.M. Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations. Org. Biomol. Chem. 2018;16(44):8525-8536.
http://dx.doi.org/10.1039/C8OB02310G