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Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase.


ABSTRACT: Virtual screening of a library of commercially available compounds versus the structure of Mycobacterium tuberculosis lumazine synthase identified 2-(2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)acetic acid (9) as a possible lead compound. Compound 9 proved to be an effective inhibitor of M. tuberculosis lumazine synthase with a K(i) of 70microM. Lead optimization through replacement of the carboxymethylsulfonamide sidechain with sulfonamides substituted with alkyl phosphates led to a four-carbon phosphate 38 that displayed a moderate increase in enzyme inhibitory activity (K(i) 38microM). Molecular modeling based on known lumazine synthase/inhibitor crystal structures suggests that the main forces stabilizing the present benzindolone/enzyme complexes involve pi-pi stacking interactions with Trp27 and hydrogen bonding of the phosphates with Arg128, the backbone nitrogens of Gly85 and Gln86, and the side chain hydroxyl of Thr87.

SUBMITTER: Talukdar A 

PROVIDER: S-EPMC2868945 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase.

Talukdar Arindam A   Morgunova Ekaterina E   Duan Jianxin J   Meining Winfried W   Foloppe Nicolas N   Nilsson Lennart L   Bacher Adelbert A   Illarionov Boris B   Fischer Markus M   Ladenstein Rudolf R   Cushman Mark M  

Bioorganic & medicinal chemistry 20100408 10


Virtual screening of a library of commercially available compounds versus the structure of Mycobacterium tuberculosis lumazine synthase identified 2-(2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)acetic acid (9) as a possible lead compound. Compound 9 proved to be an effective inhibitor of M. tuberculosis lumazine synthase with a K(i) of 70microM. Lead optimization through replacement of the carboxymethylsulfonamide sidechain with sulfonamides substituted with alkyl phosphates led to a four-car  ...[more]

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