The chemical hunt for the identification of drugable targets

Meisner, Nicole-Claudia; Hintersteiner, Martin; Uhl, Volker; Weidemann, Thomas; Schmied, Mario; Gstach, Hubert; Auer, Manfred

doi:10.1016/j.cbpa.2004.06.011

Cited by 31 publications

(32 citation statements)

References 43 publications

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“…From a stock library of 2.2 Mio bead immobilized heterocyclic compounds, a representative, diversity-optimized subset of 89,000 compounds ("master plate") ‡ was screened by CONA (confocal nanoscanning/bead picking). 41 CONA represents a high-resolution, high-speed and quantitative technology for high-throughput screening of one-bead-onecompound libraries. In CONA, the confocal detection volume is used to scan a layer of library beads in a microtiter plate to generate a cross-section image at the equatorial plane of the beads (Fig.…”

Section: Resultsmentioning

confidence: 99%

Terminal Adenosyl Transferase Activity of Posttranscriptional Regulator HuR Revealed by Confocal On-Bead Screening

Meisner

Hintersteiner

Seifert

et al. 2009

Journal of Molecular Biology

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Section: Resultsmentioning

confidence: 99%

Terminal Adenosyl Transferase Activity of Posttranscriptional Regulator HuR Revealed by Confocal On-Bead Screening

Meisner

Hintersteiner

Seifert

et al. 2009

Journal of Molecular Biology

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“…To explore the potential of inhibiting importin β function with small molecule high affinity binders, we performed a CONA on-bead screen (Figure 1) with Alexa-488 labeled importin β (9, 20–23) (Protein labelling and characterization are described in the supporting information text and in Figures S1–S4). We screened a 45,600 compound containing diversity-optimized subset from our much larger stock of one bead, one compound libraries (2.2 million compounds).…”

Section: Resultsmentioning

confidence: 99%

Identification of a Small Molecule Inhibitor of Importin β Mediated Nuclear Import by Confocal On-Bead Screening of Tagged One-Bead One-Compound Libraries

et al. 2010

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In eukaryotic cells, proteins and RNA are transported between the nucleus and the cytoplasm by nuclear import and export receptors. Over the past decade, small molecules that inhibit the nuclear export receptor CRM1 have been identified, most notably leptomycin B. However, up to now no small molecule inhibitors of nuclear import have been described. Here we have used our automated Confocal Nanoscanning and bead picking method (CONA) for on-bead screening of a one bead/one compound library to identify the first such import inhibitor, karyostatin 1A. Karyostatin 1A binds importin β with high nanomolar affinity and specifically inhibits importin α/β mediated nuclear import at low micromolar concentrations in vitro and in living cells, without perturbing transportin mediated nuclear import or CRM1 mediated nuclear export. Surface plasmon resonance binding experiments suggest that karyostatin 1A acts by disrupting the interaction between importin β and the GTPase Ran. As a selective inhibitor of the importin α/β import pathway, karyostatin 1A will provide a valuable tool for future studies of nucleocytoplasmic trafficking.

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“…Equally important but not covered in this review are aspects of target identification, target druggability, and ligand preselection. Even in the field of "classical" targets the first two topics have only been touched recently [239,240], and computational approaches are emerging [176,241]. However, they may become even more important in the case of protein-protein targets due to the large variability of PPI.…”

Section: Abbreviationsmentioning

confidence: 99%

Targeting Protein-Protein Interactions with Small Molecules: Challenges and Perspectives for omputational Binding Epitope Detection and Ligand Finding

González-Ruiz

Gohlke²

2006

CMC

172

114

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A promising way to interfere with biological processes is through the control of protein-protein interactions by means of small molecules that modulate the formation of protein-protein complexes. Although the feasibility of this approach has been demonstrated in principle by recent results, many of the small-molecule modulators known to date have not been found by rational design approaches. In large part this is due to the challenges that one faces in dealing with protein binding epitopes compared to, e.g., enzyme binding pockets. Recent advances in the understanding of the energetics and dynamics of protein binding interfaces and methodological developments in the field of structure-based drug design methods may open up a way to apply rational design approaches also for finding protein-protein interaction modulators. These advances and developments include (I) computational approaches to dissect binding interfaces in terms of energetic contributions of single residues (to identify "hot spot" residues), (II) prediction of potential binding sites from unbound protein structures, (III) recognition of allosteric binding sites as alternatives to directly targeting interfaces, (IV) docking approaches that consider protein flexibility and improved descriptions of the solvent influence on electrostatic interactions, and (V) data-driven docking approaches. Here, we will summarize these developments with a particular emphasis on their applicability to screen for or design small-molecule modulators of protein-protein interactions.

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The chemical hunt for the identification of drugable targets

Cited by 31 publications

References 43 publications

Terminal Adenosyl Transferase Activity of Posttranscriptional Regulator HuR Revealed by Confocal On-Bead Screening

Terminal Adenosyl Transferase Activity of Posttranscriptional Regulator HuR Revealed by Confocal On-Bead Screening

Identification of a Small Molecule Inhibitor of Importin β Mediated Nuclear Import by Confocal On-Bead Screening of Tagged One-Bead One-Compound Libraries

Targeting Protein-Protein Interactions with Small Molecules: Challenges and Perspectives for omputational Binding Epitope Detection and Ligand Finding

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