Virtual screening,selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase |
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| Authors: | Arindam Talukdar Ekaterina Morgunova Jianxin Duan Winfried Meining Nicolas Foloppe Lennart Nilsson Adelbert Bacher Boris Illarionov Markus Fischer Rudolf Ladenstein Mark Cushman |
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| Affiliation: | 1. Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and The Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;2. Karolinska Institute, Department of Bioscience, Hälsovägen 7-9, S-14157 Huddinge, Sweden;3. Institute of Biochemistry and Food Chemistry, Food Chemistry Division, University of Hamburg, Grindelallee 117, D-20146 Hamburg, Germany;4. Anterio Consult & Research GmbH, Augustaanlage 23, 68165 Mannheim, Germany;5. Lehrstuhl für Biologische Chemie, Technische Universität München, 85350 Freising-Weihenstephan, Germany |
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| 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. |
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