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

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 receptor-independent (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 EL_E1,4, EL_tors, EL_vdW, EL_el, and EL_el+Hb appear to be more relevant to the biological activity. These findings can be meaningful for developing QSAR studies and for designing new antituberculosis agents. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006