Pasqualoto K. F. M., Ferreira M. M. C., Santos Filho O. A., Hopfinger A. J., "Molecular dynamics simulations of a set of isoniazid derivatives bound to InhA, the enoyl-acp reductase from M.tuberculosis". São Pedro, SP, 20-23/11/2005: XIII Simpósio Brasileiro de Química Teórica (XIII SBQT) [13th Brazilian Symposium of Theoretical Chemistry], Livro de Resumos [Book of Abstracts], 202. Poster 202.

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Molecular dynamics simulation of a set of isoniazid derivatives bound to InhA, the enoyl-acp
reductase from M. tuberculosis

Kerly F. M. Pasqualoto*¹ (PQ), Márcia M. C. Ferreira¹ (PQ), Osvaldo A. Santos-Filho² (PQ), Anton J.
Hopfinger² (PQ)
*kerlyfmp@iqm.unicamp.br

¹Laboratório de Quimiometria Teórica e Aplicada (LQTA), Departamento de Físico-Química, Instituto de
Química (IQ), Universidade Estadual de Campinas (UNICAMP), Campinas - SP
²Laboratory of Molecular Modeling and Design (M/C-781), Department of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, The University of Illinois at Chicago (UIC), Chicago - IL

KEYWORDS: molecular dynamics simulation, hydrazides, tuberculosis

Ligand-receptor  molecular  dynamics  simulations  (MDSs)  were  carried out for a set of hydrazides bound to
the enoyl-acp reductase from  M. tuberculosis,  InhA (PDB entry code 1zid).  It  was presumed that all ligands
investigated would act like the lead drug isoniazid, as reported by Rozwarski and co-workers (1998). After the
hydrazide group is lost,  the activated from (acylpyridine anion or radical) would be covalently attached  to the
C4  of the nicotinamide  ring  of  the  cofactor  NAD,  resulting  in  formation  of  an  acylpyridine-NAD  adduct,
which  is  a  strongly  bound  inhibitor.   The  hypothesized   active  conformations  resulting  from  a  previous
receptor-independent  4D-QSAR  analysis  and  related optimum  model/alignment  [J. Med. Chem., 47, 3755,
2004] were used in this study. The MDSs protocol employed 500000 steps for each ligand-receptor  complex,
the step size was 0.001 ps (1fs),  and the simulation temperature was 310 K,  the same used in the biological
assay.   An  output trajectory file was saved every  20  simulation steps resulting  25000  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 total energy contributions  whose  seem  to  be  more relevant are  van der  Waals  interaction
energy and  1-4  interaction energy  (Lennard-Jones).  These  findings can be meaningful  for designing new
antituberculosis agents.