Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase Journal Article
| Authors: | Bryk, R.; Arango, N.; Venugopal, A.; David Warren, J.; Park, Y. H.; Patel, M. S.; Lima, C. D.; Nathan, C. |
| Article Title: | Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase |
| 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 Å 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. © 2010 American Chemical Society. |
| Keywords: | unclassified drug; animals; mice; cell survival; cells, cultured; enzyme inhibition; models, biological; protein binding; enzyme inhibitor; structure-activity relationship; bacteria (microorganisms); mycobacterium tuberculosis; adenosine; enzyme inhibitors; crystallography, x-ray; mutagenesis, site-directed; binding energy; binding sites; molecular structure; protein structure; macrophages; x ray crystallography; bacterial infections; enzymes; reduced nicotinamide adenine dinucleotide; nad; nicotinamide adenine dinucleotide; amides; mycobacterial; nanomolar inhibitors; intermediary metabolism; antioxidant defense; bacterial enzymes; combinatorial chemical libraries; electron-transfer; high-throughput screening; human homologue; inhibitor complex; lipoamide dehydrogenase; nonconservation; selective inhibition; selective inhibitors; bacteriology; coordination reactions; optical projectors; dihydrolipoamide dehydrogenase; triazaspiromethoxybenzoyl derivative; antitubercular agents; thioctic acid |
| Journal Title: | Biochemistry |
| Volume: | 49 |
| Issue: | 8 |
| ISSN: | 0006-2960 |
| Publisher: | American Chemical Society |
| Date Published: | 2010-03-02 |
| Start Page: | 1616 |
| End Page: | 1627 |
| Language: | English |
| DOI: | 10.1021/bi9016186 |
| PUBMED: | 20078138 |
| PROVIDER: | scopus |
| PMCID: | PMC2827632 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "CODEN: BICHA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work