Related ArticlesNMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein.
J Med Chem. 1997 Sep 26;40(20):3144-50
Authors: Hajduk PJ, Dinges J, Miknis GF, Merlock M, Middleton T, Kempf DJ, Egan DA, Walter KA, Robins TS, Shuker SB, Holzman TF, Fesik SW
The E2 protein is required for the replication of human papillomaviruses (HPVs), which are responsible for anogenital warts and cervical carcinomas. Using an NMR-based screen, we tested compounds for binding to the DNA-binding domain of the HPV-E2 protein. Three classes of compounds were identified which bound to two distinct sites on the protein. Biphenyl and biphenyl ether compounds containing a carboxylic acid bind to a site near the DNA recognition helix and inhibit the binding of E2 to DNA. Benzophenone-containing compounds which lack a carboxylic acid group bind to the beta-barrel formed by the dimer interface and exhibit negligible effects on the binding of E2 to DNA. Structure-activity relationships from the biphenyl and biphenyl ether compounds were combined to produce a compound [5-(3'-(3",5"-dichlorophenoxy)-phenyl)-2,4-pentadienoic acid] with an IC50 value of approximately 10 microM. This compound represents a useful lead for the development of antiviral agents that interfere with HPV replication and further illustrates the usefulness of the SAR by NMR method in the drug discovery process.
Advancing fragment binders to lead-like compounds using ligand and protein-based NMR spectroscopy.
Advancing fragment binders to lead-like compounds using ligand and protein-based NMR spectroscopy.
Advancing fragment binders to lead-like compounds using ligand and protein-based NMR spectroscopy.
Methods Enzymol. 2011;493:469-85
Authors: Maurer T
The application of NMR in fragment-based lead discovery (FBLD) has quickly developed from a sensitive method for the identification of low-affinity binders to an important tool in the hit-to-lead process. NMR can play a constructive role in the process from identifying those fragments with the best...
[NMR paper] NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element bi
NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element binding protein binding to the human oncogene c-myc promoter.
Related Articles NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element binding protein binding to the human oncogene c-myc promoter.
J Med Chem. 2004 Sep 23;47(20):4851-7
Authors: Huth JR, Yu L, Collins I, Mack J, Mendoza R, Isaac B, Braddock DT, Muchmore SW, Comess KM, Fesik SW, Clore GM, Levens D, Hajduk PJ
Reversal of aberrant gene expression that is induced by the...
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[NMR paper] NMR-based methods and strategies for drug discovery.
NMR-based methods and strategies for drug discovery.
Related Articles NMR-based methods and strategies for drug discovery.
Chem Soc Rev. 2003 Nov;32(6):365-72
Authors: Salvatella X, Giralt E
Nuclear Magnetic Resonance (NMR) spectroscopy has long been a favourite tool of chemists interested in host-guest systems because it permits access to a wealth of information about the molecular recognition reaction. NMR has evolved dramatically in the last 15 years and, in parallel with the development of NMR methods for the determination of protein...
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[NMR paper] NMR-based screening methods for lead discovery.
NMR-based screening methods for lead discovery.
Related Articles NMR-based screening methods for lead discovery.
EXS. 2003;(93):183-202
Authors: Vogtherr M, Fiebig K
Diversity and robustness of NMR based screening methods make these techniques highly attractive as tools for drug discovery. Although not all screening techniques discussed here may be applicable to any given target, there is however a good chance that at least one of the described methods will prove productive in finding several medium affinity ligands. A comparison of each of...
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[NMR paper] NMR-based modification of matrix metalloproteinase inhibitors with improved bioavaila
NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability.
Related Articles NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability.
J Med Chem. 2002 Dec 19;45(26):5628-39
Authors: Hajduk PJ, Shuker SB, Nettesheim DG, Craig R, Augeri DJ, Betebenner D, Albert DH, Guo Y, Meadows RP, Xu L, Michaelides M, Davidsen SK, Fesik SW
The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al....
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[NMR paper] The SHAPES strategy: an NMR-based approach for lead generation in drug discovery.
The SHAPES strategy: an NMR-based approach for lead generation in drug discovery.
Related Articles The SHAPES strategy: an NMR-based approach for lead generation in drug discovery.
Chem Biol. 1999 Oct;6(10):755-69
Authors: Fejzo J, Lepre CA, Peng JW, Bemis GW, Ajay , Murcko MA, Moore JM
BACKGROUND: Recently, it has been shown that nuclear magnetic resonance (NMR) may be used to identify ligands that bind to low molecular weight protein drug targets. Recognizing the utility of NMR as a very sensitive method for detecting binding, we have...
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[BMNRC community] NMR-based screening: a powerful tool in fragment-based drug discovery
NMR-based screening: a powerful tool in fragment-based drug discovery
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NMR-based discovery of lead inhibitors that block DNA binding of the human papillomav
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