Molecular Dynamics and Combined QM/MM Studies on the Deactivation of anti-Tubercular Drug Isoniazid by Arylamine N-Acetyltransferases

Both a molecule dynamic study and a combined quantum mechanics and molecule mechanics (QM/MM) study on the acetylating deactivation mechanism of isoniazid were presented. This type of reaction was catalyzed by arylamine N-acetyltransferases (NATs) and the results strongly support a direct acetyl group transfer process rather than a stepwise one. The isoniazid was strictly restrained in proper relative position to accept the acetyl group by a Hydrogen-bond network formed by the residues at the active center. The residues, His110 and Cys70, would be functioned as 'general base' rather than 'general acid'. If all the residues (including H2O molecules) were removed from the system, the activation energy will be increased from 145.1 to 243.3 kJ/mol. The calculations met the experimental data with good agreement.