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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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