Isolation of a Small‐Molecule Inhibitor of the Antiapoptotic Protein Bcl‐xL from a DNA‐Encoded Chemical Library

Melkko, Samu; Mannocci, Luca; Dumelin, Christoph E.; Villa, Alessandra; Sommavilla, Roberto; Zhang, Yixin; Grütter, Markus G.; Keller, N.; Jermutus, Lutz; Jackson, Ronald H.; Scheuermann, Jörg; Neri, Dario

doi:10.1002/cmdc.200900520

Cited by 53 publications

(48 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dumelin and D. Neri30. Since then, the protocol was used to screen different DECLs, allowing for the identification of small molecule binders against alpha-1-acid glycoprotein31, B-cell lymphoma-extra large15,64, bovine serum albumin19, carbonic anhydrase II30, carbonic anhydrase IX17,31, human serum albumin15,19,20,22,30, interleukin 216, matrix metalloproteinase 365, prostate-specific membrane antigen20, rabbit serum albumin19, streptavidin66,67, tankyrase 120,21, trypsin15,68,69 and tumor necrosis factor alpha15. Over the past decade, literally all parts of the protocol were improved significantly: sepharose beads were replaced by magnetic beads, automated followed after manual selections and selection analysis evolved from microarray-based decoding to more cost-efficient HTDS approaches.…”

Section: Introductionmentioning

confidence: 99%

Automated screening for small organic ligands using DNA-encoded chemical libraries

et al. 2016

Self Cite

View full text Add to dashboard Cite

DNA-encoded chemical libraries (DECLs) are collections of organic compounds that are individually linked to different oligonucleotides, serving as amplifiable identification barcodes. As all compounds in the library can be identified by their DNA tags, they can be mixed and used in affinity-capture experiments on target proteins of interest. In this protocol, we describe the screening process that allows the identification of the few binding molecules within the multiplicity of library members. First, the automated affinity selection process physically isolates binding library members. Second, the DNA codes of the isolated binders are PCR-amplified and subjected to high-throughput DNA sequencing. Third, the obtained sequencing data are evaluated using a C++ program and the results are displayed using MATLAB software. The resulting selection fingerprints facilitate the discrimination of binding from nonbinding library members. The described procedures allow the identification of small organic ligands to biological targets from a DECL within 10 d.

show abstract

Section: Introductionmentioning

confidence: 99%

Automated screening for small organic ligands using DNA-encoded chemical libraries

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Success stories have even been reported for carefully designed, smaller libraries containing only thousands of compounds. Using such focused libraries, our group has reported the de novo discovery of micromolar binders against Bcl-xL,[19] Interleukin-2 [20] and TNF. [21] In 2015, a two building block library, containing 103200 compounds, allowed the isolation of binders against a number of proteins, including prostate-specific membrane antigen and tankyrase-1.…”

Section: Single Pharmacophore Dna-encoded Chemical Librariesmentioning

confidence: 99%

DNA-encoded chemical libraries: foundations and applications in lead discovery

Zimmermann

Neri

2016

Drug Discovery Today

Self Cite

116

View full text Add to dashboard Cite

DNA-encoded chemical libraries have emerged as a powerful means for hit identification in the pharmaceutical industry and in academia. Similar to biological display techniques (such as phage display technology), DNA-encoded chemical libraries contain a link between the displayed chemical building block and an amplifiable genetic "barcode" on DNA. Using routine procedures, libraries containing millions to billions of compounds can be easily produced within a few weeks. The resulting compound libraries are screened in a single test tube against proteins of pharmaceutical interest and hits can be identified by PCR amplification of DNA-barcodes and subsequent high-throughput sequencing. Various types of DNA-encoded chemical libraries can be considered for practical applications. For example, researchers may choose between libraries containing two or three sets of building blocks. The latter approach enables the synthesis of larger libraries, but typically yields hits, which are bigger than 500 Dalton. Moreover, it is possible to display pairs of molecules on complementary DNA strands, thus enabling the combinatorial assembly of library members.

show abstract

“…$ If Ki was not available, IC50 is reported instead. 26,27,28,29,30,31,32,33,34 Using automatic pharmacophore generation and further refinements of the hypotheses, a fivefeature pharmacophore can actually be defined using this dataset. The model can be described as a four-branched star.…”

Section: Is a Unique Binding Site Possible? Building Of A Pharmacophomentioning

confidence: 99%

A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors

Levoin

Gautier

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors.

show abstract

Isolation of a Small‐Molecule Inhibitor of the Antiapoptotic Protein Bcl‐xL from a DNA‐Encoded Chemical Library

Cited by 53 publications

References 49 publications

Automated screening for small organic ligands using DNA-encoded chemical libraries

Automated screening for small organic ligands using DNA-encoded chemical libraries

DNA-encoded chemical libraries: foundations and applications in lead discovery

A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors

Contact Info

Product

Resources

About