ArticleBiochemistry2010
Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase .
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 34 citations in OpenAlex.
- Insights into Active Site Cysteine Residues inInternational journal of molecular sciences · 2025Review
- Spirocyclic compounds: potential drug leads in the fight againstFuture medicinal chemistry · 2025Review
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- Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions.ACS infectious diseases · 2021Article
- Pyruvate dehydrogenase complex-enzyme 2, a new target for Listeria spp. detection identified using combined phage display technologies.Scientific reports · 2020Article
- Kunkel Lecture: Fundamental immunodeficiency and its correction.The Journal of experimental medicine · 2017Review
- Emerging Approaches to Tuberculosis Drug Development: At Home in the Metabolome.Trends in pharmacological sciences · 2017Review
- Article
- Reconstitution of a Mycobacterium tuberculosis proteostasis network highlights essential cofactor interactions with chaperone DnaK.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- The tuberculosis drug discovery and development pipeline and emerging drug targets.Cold Spring Harbor perspectives in medicine · 2015Review
- Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase.Biochemistry · 2013Article
- A genomic scale map of genetic diversity in Trypanosoma cruzi.BMC genomics · 2012Article
- WithdrawnInfectious disorders drug targets · 2012Article
- Central carbon metabolism in Mycobacterium tuberculosis: an unexpected frontier.Trends in microbiology · 2011Article
- Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes.Cell host & microbe · 2011Article
- Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Mycobacterium tuberculosis (Mtb) remains the leading single cause of death from bacterial infection. Here we explored the possibility of species-selective inhibition of lipoamide dehydrogenase (Lpd), an enzyme central to Mtb's intermediary metabolism and antioxidant defense. High-throughput screening of combinatorial chemical libraries identified triazaspirodimethoxybenzoyls as high-nanomolar inhibitors of Mtb's Lpd that were noncompetitive versus NADH, NAD(+), and lipoamide and >100-fold selective compared to human Lpd. Efficacy required the dimethoxy and dichlorophenyl groups. The structure of an Lpd-inhibitor complex was resolved to 2.42 A by X-ray crystallography, revealing that the inhibitor occupied a pocket adjacent to the Lpd NADH/NAD(+) binding site. The inhibitor did not overlap with the adenosine moiety of NADH/NAD(+) but did overlap with positions predicted to bind the nicotinamide rings in NADH and NAD(+) complexes. The dimethoxy ring occupied a deep pocket adjacent to the FAD flavin ring where it would block coordination of the NADH nicotinamide ring, while the dichlorophenyl group occupied a more exposed pocket predicted to coordinate the NAD(+) nicotinamide. Several residues that are not conserved between the bacterial enzyme and its human homologue were predicted to contribute both to inhibitor binding and to species selectivity, as confirmed for three residues by analysis of the corresponding mutant Mtb Lpd proteins. Thus, nonconservation of residues lining the electron-transfer tunnel in Mtb Lpd can be exploited for development of species-selective Lpd inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.