A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductase

Levy, Colin; Baldock, Clair; Wallace, Alistair J.; Sedelnikova, S.E.; Viner, Russell; Clough, James R.; Stuitje, Antoine R.; Slabas, Antoni R.; Rice, David W.; Rafferty, John B.

doi:10.1006/jmbi.2001.4643

Cited by 65 publications

(55 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most salient features that had emerged from the atomic structures of ENR-NAD(H) complexed with triclosan and with other inhibitors like diazoborines, imidazoles, and aminopyridines were: 1) p-p stacking interaction between one of the aromatic rings of the inhibitors with the nicotinamide ring of the cofactor NADH and 2) a Hydrogen bond between the active site residue-Tyr277 and the inhibitor (15,(38)(39)(40). Our previous work to identify new scaffolds of inhibitors against PfENR, based on the above key features of interactions of the inhibitor with active-site residues and NADH led to the discovery of a new class of inhibitors.…”

Section: Resultsmentioning

confidence: 99%

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

et al. 2010

View full text Add to dashboard Cite

SummarySignificance of type II fatty acid synthase pathway in the life cycle of malarial parasite has long been established. Enoyl acyl carrier protein (ACP) reductase of Plasmodium falciparum (PfENR) is the rate determining enzyme of its elongation module. Hence, PfENR has been a target for the development of antimalarials as well as vaccines. Towards this endeavour, we had recently identified rhodanine class of compounds as inhibitors of PfENR. Here, we report a number of new inhibitors belonging to this class. These inhibitors have been divided into two broad subclasses: rhodanine-furans and rhodanine-phenyls. The inhibitory activity of all compounds was determined against purified PfENR. IC 50 of these compounds were found to be in nanomolar to low-micromolar range. The structure-activity relationship of both the classes has been explored in detail for the first time. Separate 3D pharmacophore models for this enzyme have been generated for both rhodanine furans and phenyls. The pharmacophore model for rhodanine furan has a Hydrogen bond donor, two Hydrogen bond acceptors, two metal ligators, three hydrophobic, and two aromatic ring features, whereas the pharmacophore model for the phenyl subclass has two hydrogen bond donors, two hydrogen bond acceptor, a metal ligator, two hydrophobic, and two aromatic ring features. These models could be used for in silico screening of compound libraries for PfENR inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

et al. 2010

View full text Add to dashboard Cite

show abstract

“…For FabI, it was shown that the NAD ϩ cofactor has to bind to the enzyme to enable interaction with the inhibitor (12,13). Structural studies showed that in the active site of FabI, the boron atom of diazaborine forms a covalent bond with the 2Ј-OH of the nicotinamide ribose moiety of the NAD ϩ cofactor (26,27). It is however currently unknown whether or not binding of diazaborine to Drg1 also involves the formation of a covalent bond between ATP and the inhibitor.…”

Section: Discussionmentioning

confidence: 99%

The Drug Diazaborine Blocks Ribosome Biogenesis by Inhibiting the AAA-ATPase Drg1

Loibl

Klein

Prattes

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Diazaborine is the only known inhibitor of eukaryotic ribosome biogenesis, but its target is unknown. Results: Diazaborine binds the AAA-ATPase Drg1 and inhibits its ATP hydrolysis, thereby blocking release of Rlp24 from pre-60S particles. Conclusion: Diazaborine blocks ribosome biogenesis by inhibiting the physiological activity of Drg1. Significance: Our results highlight the potential of the ribosome biogenesis pathway as target for novel inhibitors.

show abstract

“…The mechanism of enzyme inhibition with specific focus on ecFabI has been studied in detail using X-ray crystallography and site-directed mutagenesis [20, 60-63]. The compounds form an adduct with the cofactor through a dative bond between the NAD + 2’-ribose hydroxyl group and the diazaborine boron atom (Fig.…”

Section: Diazaborinesmentioning

confidence: 99%

Targeting InhA, the FASII Enoyl-ACP Reductase: SAR Studies on Novel Inhibitor Scaffolds

Pan

Tonge²

2012

CTMC

View full text Add to dashboard Cite

The bacterial type II fatty acid biosynthesis (FASII) pathway is an essential but unexploited target for drug discovery. In this review we summarize SAR studies on inhibitors of InhA, the enoyl-ACP reductase from the FASII pathway in M. tuberculosis. Inhibitor scaffolds that are described include the diaryl ethers, pyrrolidine carboxamides, piperazine indoleformamides, pyrazoles, arylamides, fatty acids, and imidazopiperidines, all of which form ternary complexes with InhA and the NAD cofactor, as well as isoniazid and the diazaborines which covalently modify the cofactor. Analysis of the structural data has enabled the development of a common binding mode for the ternary complex inhibitors, which includes a hydrogen bond network, a large hydrophobic pocket and a third ‘size-limited’ binding area comprised of both polar and non-polar groups. A critical factor in InhA inhibition involves ordering of the substrate binding loop, located close to the active site, and a direct link is proposed between loop ordering and slow onset enzyme inhibition. Slow onset inhibitors have long residence times on the enzyme target, a property that is of critical importance for in vivo activity.

show abstract

A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductase

Cited by 65 publications

References 19 publications

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

SAR and pharmacophore models for the rhodanine inhibitors of Plasmodium falciparum enoyl‐acyl carrier protein reductase

The Drug Diazaborine Blocks Ribosome Biogenesis by Inhibiting the AAA-ATPase Drg1

Targeting InhA, the FASII Enoyl-ACP Reductase: SAR Studies on Novel Inhibitor Scaffolds

Contact Info

Product

Resources

About