Abstract
The cell wall of mycobacterium offers well validated targets which can be exploited for discovery of new lead compounds. MurC-MurF ligases catalyze a series of irreversible steps in the biosynthesis of peptidoglycan precursor, i.e. MurD catalyzes the ligation of D-glutamate to the nucleotide precursor UMA. The three dimensional structure of Mtb-MurD is not known and was predicted by us for the first time using comparative homology modeling technique. The accuracy and stability of the predicted Mtb-MurD structure was validated using Procheck and molecular dynamics simulation. Key interactions in Mtb-MurD were studied using docking analysis of available transition state inhibitors of E.coli-MurD. The docking analysis revealed that analogues of both L and D forms of glutamic acid have similar interaction profiles with Mtb-MurD. Further, residues His192, Arg382, Ser463, and Tyr470 are proposed to be important for inhibitor-(Mtb-MurD) interactions. We also identified few pharmacophoric features essential for Mtb-MurD ligase inhibitory activity and which can further been utilized for the discovery of putative antitubercular chemotherapy.
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Abbreviations
- TB:
-
tuberculosis
- Mtb :
-
Mycobacterium tuberculosis
- MurD:
-
UDP-N-acetylmuramoyl-L-alanine-D-glutamate ligase
- UMA:
-
UDP-N-acetylmuramoyl-L-alanine
- DOTS:
-
directly observed treatment short course
- WHO:
-
World Health Organization
- D-Glu:
-
D-glutamate
- UMAG:
-
UDP-N-acetylmuramoyl-L-alanine-Dglutamate
- MD:
-
molecular dynamics
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Arvind, A., Kumar, V., Saravanan, P. et al. Homology modeling, molecular dynamics and inhibitor binding study on MurD ligase of Mycobacterium tuberculosis . Interdiscip Sci Comput Life Sci 4, 223–238 (2012). https://doi.org/10.1007/s12539-012-0133-x
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DOI: https://doi.org/10.1007/s12539-012-0133-x