title: 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.
authors.affiliation: 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.
authors.forename: Arindam
authors.initials: A
authors.lastname: Talukdar
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Morgunova
authors.forename: Jianxin
authors.initials: J
authors.lastname: Duan
authors.forename: Winfried
authors.initials: W
authors.lastname: Meining
authors.forename: Nicolas
authors.initials: N
authors.lastname: Foloppe
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
authors.forename: Adelbert
authors.initials: A
authors.lastname: Bacher
authors.forename: Boris
authors.initials: B
authors.lastname: Illarionov
authors.forename: Markus
authors.initials: M
authors.lastname: Fischer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Ladenstein
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009169:Mycobacterium tuberculosis / Q000201:enzymology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D009097:Multienzyme Complexes; C044822:6,7-dimethyl-8-ribityllumazine synthase