Title

Insight to pyrazinamide resistance in Mycobacterium tuberculosis by molecular docking

Authors

A. Nusrath Unissa*, N. Selvakumar, Sameer Hassan

Affiliation

¹Department of Mycobacteriology, Tuberculosis Research Centre (TRC), Indian Council of Medical Research (ICMR), Mayor V. R. Ramanathan Road, Chetput, Chennai 600 031, Tamil Nadu, India; ²Department of Mycobacteriology, TRC, ICMR; ³Department of Biomedical Informatics Centre, Indian Council of Medical Research (ICMR), Mayor V. R. Ramanathan Road, Chetput, Chennai 600 031, Tamil Nadu, India

Email

nusrathunissa@gmail.com

Article Type

Hypothesis

Date

Received April 09, 2009; Revised June 10, 2009; Accepted June 13, 2009; Published August 18, 2009

Abstract

Pyrazinamide (PZA) - an important drug in the anti-tuberculosis therapy, activated by an enzyme Pyrazinamidase (PZase). The basis of PZA resistance in Mycobacterium tuberculosis was owing to mutation in pncA gene coding for PZase. Homology modeling of PZase was performed using software Discovery Studio (DS) 2.0 based on the crystal structure of the PZase from Pyrococcus horikoshii (PDB code 1im5), in this study. The model comprises of one sheet with six parallel strands and seven helices with the amino acids Asp8, Asp49, Trp68, Lys96, Ala134, Thr135 and Cys138 at the active site. Five mutants were generated with Gly at position 8, Thr at position 96, Arg at position 104, Tyr and Ser at position 138. The Wild-type (WT) and five mutant models were docked with PZA. The results indicate that the mutants Lys96Thr, Ser104Arg Asp8Gly and Cys138Tyr may contribute high-level drug resistance than Cys138Ser. These models provide the first in-silico evidence for the binding interaction of PZA with PZase and form the basis for rationalization of PZA resistance in naturally occurring pncA mutant strains of M. tuberculosis.

Keywords

Mycobacterium tuberculosis, PZA resistance, PZase, mutants, docking

Citation

Unissa et al, Bioinformation 4(1): 24-29 (2009)

Edited by

P. Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.