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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. June 2007, Volume 6, Number 6, 151-166 |
Inhibition of Methionine S-adenosyltransferase of M. smegmatis and M. tuberculosis:
Homology Modeling, Docking and De Novo Inhibitor Design
Santosh A. Khedkar, Alpeshkumar K. Malde, and Evans C. Coutinho
Internet Electron. J. Mol. Des. 2007, 6, 151-166
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Abstract:
Mycobacterium tuberculosis (Mtb) is a successful pathogen that overcomes the
numerous challenges presented by the immune system of the host. Increasing
resistance to the currently available drugs has been a pressing force for the search
for new anti-TB drugs which are active against drug-resistant strains. Also, any
new inhibitor should be active against both the acute and chronic growth phases
of the mycobacteria. Methionine S-adenosyltransferase (MAT) is an enzyme
involved in the synthesis of S-adenosylmethionine, a methyl donor essential for
mycolipid and polyamine biosynthesis (during active growth) and for methylation
and cyclopropylation of mycolipids (necessary for survival during the dormant
phase). Inhibitors of the MAT enzyme appear to be promising anti-TB agents.
The homology models of MAT from M. smegmatis (non-virulent) and M. tuberculosis
(pathogenic form) were built using comparative protein modeling
principles. Docking studies (with the program GOLD) in conjunction with
different scoring functions (GoldScore, ChemScore and HINT score) were
employed to explore the binding modes of some known inhibitors of Msm-MAT
and to decipher the crucial interactions between the inhibitors and the enzyme.
Various terms of the scoring functions were correlated to the inhibition data. The
docking and scoring protocol established and validated for Msm-MAT can be
used to search small-molecule 3D databases to extract novel ligands for Mtb-MAT
(pathogenic form). Further, new molecules were designed for Mtb-MAT
using the de novo ligand design approach of the program Ludi.
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