Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors

Antonysamy, Stephen; Aubol, Brandon E.; Blaney, Jeff; Browner, Michelle F.; Giannetti, Anthony M.; Harris, S.F.; Hébert, Normand; Hendle, J.; Hopkins, Stephanie; Jefferson, Elizabeth A.; Kissinger, Charles R.; Lévêque, Vincent; Marciano, David; McGee, Ethel; Nájera, Isabel; Nolan, Brian E.; Tomimoto, Mitsumi; Torres, Eduardo; Wright, Tobi A

doi:10.1016/j.bmcl.2008.03.056

Cited by 57 publications

(35 citation statements)

References 15 publications

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“…These are now augmented with techniques such as NMR that monitors ligand signals (STD, LOGSY, etc. [6]) and Surface Plasmon Resonance [7]. Most practitioners are now converging on a similar approach, where a relatively rapid biophysical method is used to identify which fragments are binding competitively to a target site, with confirmed hits taken into crystallisation trials to confirm binding and characterise binding modes.…”

Section: Introductionmentioning

confidence: 98%

Lessons for fragment library design: analysis of output from multiple screening campaigns

Chen¹,

Hubbard

2009

J Comput Aided Mol Des

116

105

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Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets. Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening. We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally defined druggability index for the target. In general, the physicochemical properties of the fragment hits display the same profile as the library, as is expected for a truly diverse library which probes the relevant chemical space. An analysis of the fragment hits against various protein classes has shown that the physicochemical properties of the fragments are complementary to the properties of the target binding site. The effectiveness of some fragments appears to be achieved by an appropriate mix of pharmacophore features and enhanced aromaticity, with hydrophobic interactions playing an important role. The analysis emphasizes that it is possible to identify small fragments that are specific for different binding sites. To conclude, we discuss how the results could inform further development and improvement of our fragment library.

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Section: Introductionmentioning

confidence: 98%

Lessons for fragment library design: analysis of output from multiple screening campaigns

Chen¹,

Hubbard

2009

J Comput Aided Mol Des

116

105

View full text Add to dashboard Cite

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“…Sufficient ligand density on the chip surface or a low molecular weight target protein binding to the immobilised antigen may also reduce the sensitivity of the SPR system (due to low chip surface densities) and impact the limit of detection, although many issues may be resolved using careful experimental design coupled with the use of instrumentation that shows improved sensitivity. The recent move of SPR instruments into the fragment screening arena has arisen as a direct result of these two factors [16][17][18][19]. The basic principles of SPR detection and its applications in the various stages of biopharmaceutical production and process development are described in more detail in the following sections.…”

Section: Introductionmentioning

confidence: 99%

Biopharmaceutical production: Applications of surface plasmon resonance biosensors

Thillaivinayagalingam

Gommeaux

McLoughlin

et al. 2010

Journal of Chromatography B

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“…Several screens have been reported with several targets including GPCRs, kinases, a reverse transcriptase, carbonic anhydrase, proteases, and a polymerase [1][2][3][4][5][6][7][8]. This technique measures the interaction of a fragment with a protein target on a biosensor, and kinetic constants are derived from binding data.…”

Section: Introductionmentioning

confidence: 99%

Biosensor-based small molecule fragment screening with biolayer interferometry

Wartchow

Podlaski

et al. 2011

J Comput Aided Mol Des

117

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Biosensor-based fragment screening is a valuable tool in the drug discovery process. This method is advantageous over many biochemical methods because primary hits can be distinguished from non-specific or non-ideal interactions by examining binding profiles and responses, resulting in reduced false-positive rates. Biolayer interferometry (BLI), a technique that measures changes in an interference pattern generated from visible light reflected from an optical layer and a biolayer containing proteins of interest, is a relatively new method for monitoring small molecule interactions. The BLI format is based on a disposable sensor that is immersed in 96-well or 384-well plates. BLI has been validated for small molecule detection and fragment screening with model systems and well-characterized targets where affinity constants and binding profiles are generally similar to those obtained with surface plasmon resonsance (SPR). Screens with challenging targets involved in protein-protein interactions including BCL-2, JNK1, and eIF4E were performed with a fragment library of 6,500 compounds, and hit rates were compared for these targets. For eIF4E, a protein containing a PPI site and a nucleotide binding site, results from a BLI fragment screen were compared to results obtained in biochemical HTS screens. Overlapping hits were observed for the PPI site, and hits unique to the BLI screen were identified. Hit assessments with SPR and BLI are described.

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Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors

Cited by 57 publications

References 15 publications

Lessons for fragment library design: analysis of output from multiple screening campaigns

Lessons for fragment library design: analysis of output from multiple screening campaigns

Biopharmaceutical production: Applications of surface plasmon resonance biosensors

Biosensor-based small molecule fragment screening with biolayer interferometry

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