Project

Back to overview

Combined use of NMR and DNA encoded libraries for drug discovery

Applicant Wider Gerhard
Number 144242
Funding scheme Project funding
Research institution Institut für Molekularbiologie und Biophysik ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Molecular Biology
Start/End 01.12.2012 - 31.05.2016
Approved amount 259'348.00
Show all

All Disciplines (2)

Discipline
Molecular Biology
Biophysics

Keywords (5)

NMR spectroscopy; TNF; DNA-encoded library; drug discovery; glycosylation

Lay Summary (English)

Lead
Lay summary

Molecular interactions are key processes in biology, chemistry and medicine. The challenging identification and structural characterization of interacting molecules provides the basis for a detailed understanding of these processes. In this research we want to investigate the potential of the combination of two techniques which are so far applied separately in drug discovery: NMR spectroscopy in solution and DNA-encoded chemical libraries (DECL). NMR provides structural and dynamic data on molecular interactions whereas DECL can efficiently identify ligands that bind to a particular protein. Whereas DECL delivers weak binders relatively easily, the optimization for specific and tight binding becomes more involved. The search process by DECL could be guided by structural and dynamic data that is obtained from NMR measurements in solution. The detailed procedures on how to combine the two techniques to reach this goal efficiently shall be established within this study.

For the development of procedures for a combined use of NMR and DECL in drug discovery we will search drug candidates for the tumor necrosis factor alpha (TNF-a). TNF-a is related to many human diseases and is a major target in pharmaceutical research in industry and universities. So far, only large antibody based molecules are available that inhibit TNF-a. With the combination of NMR and DECL we want to identify a small compound that tightly and specifically binds TNF-a. In a first step, drug candidates will be identified by DECL with a library developed by the co-applicant. The hits will be tested by in-vivo assays and the binding site will be structurally and dynamically characterized by NMR measurements.

The outcome of this work will make available a novel procedure that combines NMR and DECL for efficient drug discovery. Specifically, our results will provide a better basis for further rational improvements of small molecules blocking TNF-a activity and possibly deliver a drug candidate for TNF-inhibition.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Activity of Tumor Necrosis Factor α Is Modulated by Dynamic Conformational Rearrangements
Hofmann Daniela, Salmon Loïc, Wider Gerhard (2017), Activity of Tumor Necrosis Factor α Is Modulated by Dynamic Conformational Rearrangements, in Journal of the American Chemical Society, 140(1), 167-175.
Automated screening for small organic ligands using DNA-encoded chemical libraries
Decurtins W, Wichert M, Franzini RM, Buller F, Stravs MA, Zhang Y, Neri Dario, Scheuermann Jörg (2016), Automated screening for small organic ligands using DNA-encoded chemical libraries, in Nature Protocols, 11(4), 764-780.
Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation
Wichert M, Krall N, Decurtins W, Franzini RM, Pretto F, Schneider P, Neri Dario, Scheuermann Jörg (2015), Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation, in Nature Chemistry, 7(3), 241-249.
Dual-pharmacophore DNA-encoded chemical libraries
Scheuermann Jörg, Neri Dario (2015), Dual-pharmacophore DNA-encoded chemical libraries, in Curr Opin Chem Biol , 26, 99-103.
Interrogating target-specificity by parallel screening of a DNA-encoded chemical library against closely related proteins
Franzini RM, Nauer A, Scheuermann Jörg, Neri Dario (2015), Interrogating target-specificity by parallel screening of a DNA-encoded chemical library against closely related proteins, in Chem Commun (Camb), 51(38), 8014-8016.
Next generation Therapeutics
Neri Dario and Scheuermann Jörg (ed.) (2015), Next generation Therapeutics, Elsevier, Amsterdam.
Posttranslational modifications of intact proteins detected by NMR spectroscopy: application to glycosylation.
Schubert Mario, Walczak Michal J, Aebi Markus, Wider Gerhard (2015), Posttranslational modifications of intact proteins detected by NMR spectroscopy: application to glycosylation., in Angewandte Chemie (International ed. in English), 54(24), 7096-100.
Copsin, a Novel Peptide-based Fungal Antibiotic Interfering with the Peptidoglycan Synthesis
Essig Andreas, Hofmann Daniela, Münch Daniela, Gayathri Savitha, Künzler Markus, Kallio Pauli T., Sahl Hans-Georg, Wider Gerhard, Schneider Tanja, Aebi Markus (2014), Copsin, a Novel Peptide-based Fungal Antibiotic Interfering with the Peptidoglycan Synthesis, in Journal of Biological Chemistry, 289(50), 34953-34964.
Direct monitoring of protein–protein inhibition using nano electrospray ionization mass spectrometry
Cubrilovic Dragana, Barylyuk Konstantin, Hofmann Daniela, Walczak Michal Jerzy, Gräber Martin, Berg Thorsten, Wider Gerhard, Zenobi Renato (2014), Direct monitoring of protein–protein inhibition using nano electrospray ionization mass spectrometry, in Chemical Science, 5(7), 2794-2794.
DNA-Encoded Chemical Libraries: Advancing beyond Conventional Small-Molecule Libraries
Franzini RM, Neri Dario, Scheuermann Jörg (2014), DNA-Encoded Chemical Libraries: Advancing beyond Conventional Small-Molecule Libraries, in Acc Chem Res, 47(4), 1247-1255.
Systematic evaluation and optimization of modification reactions of oligonucleotides with amines and carboxylic acids for the synthesis of DNA-encoded chemical libraries
Franzini RM, Samain F, Abd Elrahman M, Mikutis G, Nauer A, Zimmermann M, Scheuermann Jörg, Hall J, Neri Dario (2014), Systematic evaluation and optimization of modification reactions of oligonucleotides with amines and carboxylic acids for the synthesis of DNA-encoded chemical libraries, in Bioconjug Chem, 25(8), 1453-1461.

Collaboration

Group / person Country
Types of collaboration
Dr. M. Schubert, University of Salzburg Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. D. Neri, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. M. Aebi, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ICMRBS 2016 Poster Human Tumor Necrosis Factor Alpha is Inactivated by Small Molecules via a Molten Globular State 21.06.2016 Kyoto, Japan Wider Gerhard; Hofmann Daniela;
Drug Discovery Chemistry Talk given at a conference Fragment-Based Drug Discovery with Dual-Display DNA-Encoded Chemical Libraries 21.04.2016 San Diego, United States of America Scheuermann Jörg;
XXIth Swiss NMR Symposium Talk given at a conference Recent method developments and biological studies in the Wider group 04.02.2016 Lausanne, Switzerland Hofmann Daniela; Wider Gerhard;
ISMAR 2015 Talk given at a conference Posttranslational Modifications of Intact Proteins Detected by NMR Spectroscopy: Application to Glycosylation 16.08.2015 Shanghai, China Wider Gerhard;
Euromar 2015 Poster Influence of Glycans on Drug Binding Studied in AGP1 05.07.2015 Prag, Czech Republic Wider Gerhard; Hofmann Daniela;
Biology Symposium 2013 Poster Drug Improvement by combining NMR and DNA-encoded chemical libraries 10.06.2014 Davos, Switzerland Wider Gerhard; Hofmann Daniela; Scheuermann Jörg;
Drug Discovery Chemistry Talk given at a conference DNA-Encoded Chemical Libraries for Fragment-Based Drug Discovery 16.04.2013 San Diego, United States of America Scheuermann Jörg;
World ADC Talk given at a conference Antibodies and Small Organic Ligands for the Targeted Delivery of Cytotoxics 28.02.2013 Frankfurt, Germany Scheuermann Jörg;


Self-organised

Title Date Place

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Spark Award 2014 Talk 06.03.2014 Zürich, Switzerland Hofmann Daniela; Wider Gerhard;


Associated projects

Number Title Start Funding scheme
139221 New electronics for 900MHz NMR spectrometer 01.12.2011 R'EQUIP
140559 Technische Entwicklungen in biomolekularer NMR Spektroskopie 01.09.2012 Project funding

Abstract

Molecular interactions are key processes in biology, chemistry and medicine. The challenging identification and structural characterization of interacting molecules provides the basis for a detailed understanding of these processes. In this proposal we want to investigate the potential of the combination of two techniques which are so far applied separately in drug discovery: NMR spectroscopy in solution and DNA-encoded chemical libraries (DECL). NMR provides structural and dynamic data on molecular interactions whereas DECL can efficiently identify ligands that bind to a particular protein. Whereas DECL delivers weak binders relatively easily, the optimization for specific and tight binding becomes more involved. The search process by DECL could be guided by structural and dynamic data that is obtained from NMR measurements in solution. The detailed procedures on how to combine the two techniques to reach this goal efficiently shall be established within this study. For the development of procedures for a combined use of NMR and DECL in drug discovery we will search drug candidates for the tumor necrosis factor alpha (TNF). TNF is related to many human diseases and is a major target in pharmaceutical research in industry and universities. So far, only large antibody based molecules are available that inhibit TNF. With the combination of NMR and DECL we want to identify a small compound that tightly and specifically binds TNF. In a first step, drug candidates will be identified by DECL with a library developed by the co-applicant in the research group of Prof. Neri (ETH Zurich). The hits will be tested by in-vivo assays and the binding site will be structurally and dynamically characterized by NMR measurements. Our preliminary NMR measurements with a published drug indicate that in solution the trimeric form of TNF remains preserved, in contrast to a previous crystallographic study where the drug disrupted the TNF trimer and forms a complex with a TNF dimer. Further, TNF is glycosylated; however, the influence of the glycan on intermolecular interactions was never investigated. With NMR in solution we will be able to clarify this situation.The outcome of this work will make available a novel procedure that combines NMR and DECL for efficient drug discovery. Specifically, our results will provide a better basis for further rational improvements of small molecules blocking TNF activity and possibly deliver a drug candidate for TNF-inhibition.
-