Title of article :
Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase Original Research Article
Author/Authors :
Arindam Talukdar، نويسنده , , Ekaterina Morgunova، نويسنده , , Jianxin Duan، نويسنده , , Winfried Meining، نويسنده , , Nicolas Foloppe and Lennart Nilsson، نويسنده , , Lennart Nilsson، نويسنده , , Adelbert Bacher، نويسنده , , Boris Illarionov، نويسنده , , Markus Fischer، نويسنده , , Rudolf Ladenstein، نويسنده , , Mark Cushman، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2010
Pages :
17
From page :
3518
To page :
3534
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 Ki of 70 μM. 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 (Ki 38 μM). Molecular modeling based on known lumazine synthase/inhibitor crystal structures suggests that the main forces stabilizing the present benzindolone/enzyme complexes involve π–π 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.
Keywords :
Lumazine synthase , Mycobacterium tuberculosis , Virtual screening , Inhibitor
Journal title :
Bioorganic and Medicinal Chemistry
Serial Year :
2010
Journal title :
Bioorganic and Medicinal Chemistry
Record number :
1307353
Link To Document :
بازگشت