96.

Pasqualoto K. F. M., Pereira F. S., Ferreira M. M. C., Santos-Filho O., Hopfinger A, "Molecular Dynamics Simulations of a Set of Isoniazid Derivatives Bound to InhA, the Enoyl-acp Reductase from M. tuberculosis, and Construction of QSAR Models Using PLS Regression and GFA Algorithm". São Pedro, SP, Brazil, 12-15/11/2006: The 3rd Brazilian Symposium on Medicinal Chemistry: Recent Advances in Drug Discovery and Development. Abstract Book, (2006) S3-169. Poster S3-169. Session: Drug Design: Tools in Chemo- and Bioinformatics.

The 3rd Brazilian Symposium on Medicinal Chemistry

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Molecular Dynamics Simulations of a Set of Isoniazid Derivatives Bound to InhA, the Enoyl-acp Reductase from M. tuberculosis, and Construction of QSAR Models Using PLS Regression and GFA Algorithm
K. F. M. Pasqualoto¹,* F. S. Pereira¹, M. M. C. Ferreira¹, O. Santos-Filho², A. Hopfinger³. (kerlyfmp@iqm.unicamp.br)
¹Laboratory for Theoretical and Applied Chemometrics, Department of Physical Chemistry, Institute of Chemistry, The State University of Campinas - UNICAMP, Campinas, SP, Brazil, ²University of British Columbia, Canada, ³University of New Mexico, USA

Key words: molecular dynamics simulation, isoniazid derivatives, QSAR analysis
Ligand-receptor molecular dynamics (MD) simulations 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 receptor-independent (RI) 4D-QSAR analysis and related optimum model/alignment were used in this study. The MD simulations protocol employed 500000 steps with a step size of 0.001 ps (1 fs). 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 from each MD simulation. The preliminary results, using the principal component analysis (PCA), indicate that the thermodynamic descriptors EL_E1,4, EL_tors, EL_el and EL_el+Hb seem to be more relevant to the biological activity. Reliable QSAR models were constructed employing the PLS regression and the genetic function approximation, GFA.

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