Actas de congresos
Molecular Dynamics Simulations Of A Set Of Isoniazid Derivatives Bound To Inha, The Enoyl-acp Reductase From M. Tuberculosis
Registro en:
International Journal Of Quantum Chemistry. , v. 106, n. 13, p. 2689 - 2699, 2006.
207608
10.1002/qua.21055
2-s2.0-33749183078
Autor
Pasqualoto K.F.M.
Ferreira M.M.C.
Santos-Filho O.A.
Hopfinger A.J.
Institución
Resumen
Ligand-receptor molecular dynamics simulations (MDS) were carried out for a set of hydrazides bound to the enoyl-acp reductase from M. tuberculosis, InhA (PDB entry code 1zid). The hypothesized active conformations resulting from a previous receptorindependent (RI) 4D-QSAR analysis and related optimum model/alignment were used in this study. The molecular dynamics simulations (MDS) protocol employed 500000 steps for each ligand-receptor complex, the step size was 0.001 ps (1 fs), and the simulation temperature was 310 K, the same temperature used in the biological assay. An output trajectory file was saved every 20 simulation steps, resulting in 25,000 conformations. The hydration shell model was used to calculate the solvation energy of the lowest-energy conformation obtained from each MDS. Structural parameters as well as binding energy contributions were considered in this analysis. The thermodynamic descriptors ELE1,4, ELtors, ELel, EL el, and ELel+Hb appear to be more relevant to the biological activity. These findings can be meaningful for developing QSAR studies and for designing new antiruberculosis agents. © 2006 Wiley Periodicals, Inc. 106 13 2689 2699 Barry III, C.E., Lee, R.E., Mdluli, K., Sampson, A.E., Schroeder, B.G., Slayden, R.A., Yuan, Y., (1998) Prog Lipid Res, 37, p. 143 McCarthy, A.D., Hardie, D.G., (1984) Trends Biochem, 9, p. 60 Magnuson, K., Jackowski, S., Rock, C.O., Cronan Jr., J.E., (1993) Microbiol Rev, 57, p. 522 Bergler, H., Fuchsbiclher, S., Högenauer, G., Turnowsky, F., (1996) Eur J Biochem, 242, p. 689 Stewart, M., Parikh, S., Xiao, G., Tonge, P.J., Kisker, C., (1999) J Mol Biol, 290, p. 859 Rozwarski, D.A., Vilchéza, C., Sugantino, M., Bitrman, R., Sacchettini, J.C., (1999) J Biol Chem, 274, p. 15582 Pasqualoto, K.F.M., Ferreira, E.I., (2001) Curr Drug Targets, 2, p. 427 Brenan, P.J., Nikaido, H., (1995) Annu Rev Biochem, 64, p. 29 Rozwarski, D.A., Grant, G.A., Barton, D.H.R., Jacobs Jr., W.R., Sacchettini, J.C., (1998) Science, 279, p. 98 Pasqualoto, K.F.M., Ferreira, E.I., Santos-Filho, O.A., Hopfinger, A.J., (2004) J Med Chem, 47, p. 3755 Jolliffe, I.T., (2002) Springer Series in Statistics-principal Components Analysis 2nd Ed., , Springer-Verlag: New York Beebe, K.R., Pell, R.J., Seasholtz, M.B., (1998) Chemometrics: A Practical Guide, , Wiley: New York Bernstein, J., Lott, W.A., Steinberg, B.A., Yale, H.L., (1952) Am Rev Tuberc, 65, p. 357 Bernstein, J., Jambor, W.P., Lott, W.A., Pansy, F., Steinberg, B.A., Yale, H.L., (1953) Am Rev Tuberc, 67, p. 354 Bernstein, J., Jambor, W.P., Lott, W.A., Pansy, F., Steinberg, B.A., Yale, H.L., (1953) Am Rev Tuberc, 67, p. 366 Klopman, G., Fercu, D., Jacob, J., (1996) Chem Phys, 204, p. 181 (2002) HyperChem Program Release 7.51 for Windows, , Hypercube: Gainesville, FL Doherty, D., (1997) MOLSIM: Molecular Mechanics and Dynamics Simulation Software. User's Guide Version 3.2, , Chem21 Group: Lake Forest, IL Dewar, M.J.S.E., Zoebisch, G., Healy, E.F., Stewart, J.J.P., (1985) AM1: J Am Chem Soc, 107, p. 3902 Weiner, S.J., Kollman, P.A., Nguyen, D.T., Case, D.A., (1986) J Comput Chem, 7, p. 230 Hopfinger, A.J., (1973) Conformational Properties of Macromolecules, p. 71. , Academic Press: New York Berendsen, H.J.C., Postman, J.P.M., Van Gunsteren, W.F., Di Nola, A., Haak, J.R., (1984) J Chem Phys, 81, p. 3684 Van Gunsteren, W.F., Berendsen, H.J.C., (1990) Angew Chem Int Ed Engl, 29, p. 992 Tokarski, J.S., Hopfinger, A.J., (1997) J Chem Inform Comput Sci, 37, p. 792 Rogers, D., Hopfinger, A.J., (1994) J Chem Inform Comput Sci, 34, p. 854