Section for Organic and Medicinal Chemistry
«With our medicinal chemistry expertise, structure-based design and organic synthesis, we develop new treatment options for patients.»
The research activities of the section for Organic and Medicinal Chemistry are focused on the organic synthesis and analyses of functional molecules at the interface between chemistry and biology with an emphasis on the development of clinical drug candidates for therapeutically relevant indications.
Areas of expertise
Medicinal Chemistry
- SNSF-Sinergia project on antiviral drug discovery at the ICBT
- Disease-causing protein beaten at its own game
Our Medicinal Chemistry activities span from hit identification, through hit to lead development and lead optimization to delivering active pharmaceutical ingredients (APIs) for in vitro and in vivo studies. Our focus is on the development of clinical candidates with our industry partners and includes the structural analysis of the target proteins (and their complexes) and results in the delivery of novel and patentable small organic ligands for clinical trials by using a combination of classical SAR profiling and state of the art fragment-based approaches.
- structural analysis of the target protein (X-ray analysis of co-crystal structures)
- NMR binding studies (ligand/protein)
- fragment-based design of novel ligands
- effective application of industry standard docking software
- multi-step organic synthesis of ligands
- establishment of structure activity relationships (SAR)
- development of data bank based IT solutions for the information management of chemical and biological data (SAR, inventory, etc.)
Selected publications
- Drug Design Inspired by Nature: Crystallographic Detection of an Auto‐Tailored Protease Inhibitor Template / F. M. Gall, D. Hohl, D. Frasson, T. Wermelinger, P. R. E. Mittl, M. Sievers, R. Riedl, Angew. Chem. Int. Ed. 2019, 58, 4051.
- A Structural View on Medicinal Chemistry Strategies against Drug Resistance / S. Agnello, M. Brand, M. F. Chellat, S. Gazzola, R. Riedl, Angew. Chem. Int. Ed. 2019, 58, 3300.
- Pseudouridimycin: The First Nucleoside Analogue That Selectively Inhibits Bacterial RNA Polymerase / M. F. Chellat, R. Riedl, Angew. Chem. Int. Ed. 2017, 56, 13184.
- Targeting Antibiotic Resistance / Chellat, Mathieu; Raguž, Luka; Riedl, Rainer - Angew. Chem. Int. Ed. 2016, 55, 6600-6626; Angew.Chem. 2016, 128, 6710–6738.
- Molecular recognition of the catalytic zinc (II) ion in MMP-13: Structure-based evolution of an allosteric inhibitor to dual binding mode inhibitors with improved lipophilic ligand efficiencies / Fischer, Thomas; Riedl, Rainer - invited article for the Special Issue "Enzyme-Inhibitor Interaction as Examples of Molecular Recognition" Int. J. Mol. Sci. 2016, 17, 314. Front cover story 3/2016.
- Merging Allosteric and Active Site Binding Motifs: De novo Generation of Target Selectivity and Potency via Natural-Product-Derived Fragments / Lanz, Jan; Riedl, Rainer - ChemMedChem. 2015, 10, 451–454. Front cover story 3/2015.
- Strategic Targeting of Multiple Water-Mediated Interactions: A Concise and Rational Structure-Based Design Approach to Potent and Selective MMP-13 Inhibitors / Fischer, Thomas; Riedl, Rainer - ChemMedChem. 2013, 8, 1457-1461. Cover story 9/2013.
Organic Synthesis + Synthetic Methodology
Our activities in the area of Organic Synthesis and Synthetic Methodology are focused around the multi-step syntheses of catalysts and APIs. Our core competence in Organic Synthesis and implementation of computational chemistry allow for a flexible research strategy for catalyst development and drug discovery. This flexible and multi-faceted approach has been applied with great success to the benefit of our industry
partners.
In addition to classical organic synthetic techniques we have invested in advanced organic synthetic technologies such as microwave reactors, microreactors, parallel synthesis, automated solid phase synthesizers and high pressure reactors.
Organic Analysis + Structure Elucidation
We have the expertise and equipment for Analyses and Structure Elucidation of Organic Molecules of both routine in house samples or those of our customers, as well as ongoing research activities in the isolation, identification and optimization of biogenic drug molecules.
Cheminformatics
The goal of our activities in Cheminformatics is the development of IT solutions for the storage and convenient analysis of large data sets. Those data sets usually arise from medicinal chemistry projects. Here, the analysis of chemical structures in combination with effective and customizable displays of biological data are particularly useful, but large chemical inventory data sets of chemical organizations are also easily handled.
CyBy2: a structure-based data management tool for chemical and biological data
Research and Business Services
Projects
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Therapy for the NRAS melanoma subtype
Melanoma is the fifth most common cancer in Switzerland and the most lethal skin cancer. NRAS (neuroblastoma ras viral oncogene homolog)-mutated melanoma is the most aggressive subtype, with no effective therapy after immunotherapy failure. The goal of this project is to develop the first effective targeted therapy ...
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Platform for drug target identification
A major problem in medicinal chemistry and drug discovery projects is the unknown identity of the molecular biological target, even when very potent ligands are available, such as those discovered in a phenotypic screen. Therefore, methods for hit optimization, such as structure-based design, or better understanding ...
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Inhibitors targeting SARS-CoV-2 proteases
So far, vaccines are available to combat the Covid-19 pandemic, which can protect against a severe course, although part of society also does not want to be vaccinated or cannot do so due to pre-existing conditions. With a drug that can fight the virus in the organism, infected patients with severe symptoms would be ...
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Developing novel and effective therapies for treatment of childhood brain cancers
Brain cancers are a leading cause of mortality in children. Brainstem glioma constitutes 10% of all pediatric central nervous system tumors, the most common type being a high grade diffuse midline glioma (DMG). Preclinical discoveries fail to translate into clinical success due to: i) drug systemic toxicity, and ii) ...
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Development of new therapeutic approaches for the treatment of cancer
Further therapeutic approaches are urgently needed for the treatment of cancer. The aim of this project is to synthesize active substances that interact with biological target proteins relevant in cancer therapy. For this purpose, multi-step organic syntheses are carried out and the active substances are optimized ...
Collaborations
We offer a multitude of possible R & D collaborations. Long term CTI funded research projects are possible as well as mid-term contract research projects. Bachelor and Master Theses complement our research collaborations.
Medicinal Chemistry
- collaboration with research based pharmaceutical companies according to our complete set of medicinal chemistry capacities (from structure based design to organic synthesis and the delivery of small molecule clinical drug candidates)
- consulting in the area of medicinal chemistry and process management for start-up as well as small and mid-sized pharmaceutical companies (computational drug design, establishing screening concepts, development of structure activity relationships, development of clinical candidates, process optimization employing SixSigma process management tools)
Organic Synthesis and Organic Analytics
- development of multi-step organic synthetic routes employing a vast range of organic procedures, such as organocatalytic and organometallic catalysts
- evaluation of advanced synthetic techniques such as microreactor and microwave assisted organic syntheses, solid phase syntheses, biocatalytic processes and high pressure transformations
- NMR (1H, 13C, 19F, 31P and 2D measurements) and LC-MS measurements
- preparative HPLC purification
Cheminformatics
- adaption of our CyBy2 IT-solution as the central tool for your needs regarding data storage and data analysis of chemical and biological data sets
Technologies
Equipment
- Thermo MSQ Plus UHPLC‐single quadrupole system
- Liberty Blue Automated Microwave Peptide Synthesizer
- Bruker AVANCE III HD 500MHz OneBay NMR Spectrometer
- Waters Xevo-Acquity UPLC-triple quadrupole system
- Gilson PLC 2020 Purification system
- LC-MS Agilent Ion Trap XCT
- Knauer preparative HPLC System: flow rate up to 500 ml/min
- Ehrfeld and Little Things Factory semi-automatic microreactor synthesis equipment
- Radleys parallel synthesis equipment
- ISCO chromatography system
- GeneVac EZ-2 evaporation system
- 6-Core workstation equipped with molecular docking software
- lab reactor LabMax: automatic synthesis (-40 °C to 140 °C)
- ChemSpeed PSW 1100: automatic peptide synthesis equipment
- Biotage, MLS System: microwave assisted synthesis equipment
- Büchi autoclave systems: up to 50 bar and maximum 1 litre
- industry sized evaporation system Büchi R-220
- Perkin-Elmer 341 polarimeter, FTIR, GC
Awards
- Poster(PDF 891,1 KB) 2013: SCG-FH Award Category «Molecules for the Life Sciences» Tackling antibiotic resistance: A joint project of the center for organic and medicinal chemistry ZHAW and the Bioversys AG.
- ZHAW press release(PDF 74,7 KB) (German) 2013: SCS awarded the Dr. Max Lüthi award for bachelor thesis on the rational design and synthesis of novel protease inhibitors.
- ZHAW press release(PDF 46,8 KB) (German) 2012: MSc thesis on the structure based design and synthesis of novel protease inhibitors received Bodenseeinnovation award.
- ZHAW press release (PDF 46,4 KB)(German) 2011: SCS awarded the Dr. Max Lüthi award for bachelor thesis on ... über die Entwicklung von Wirkstoffen zur Bekämpfung von Antibiotikaresistenzen.
Downloads
- ZHAW-Medienmitteilung (german) / ChemMedChem about the de novo design and synthesis of protease inhibitors (11.3.2015).
- ZHAW News Release / on review article on targeting antibiotic resistance published in Angewandte Chemie (8.6.2016, in German).
- ZHAW News Release / on cover story about the development of protease inhibitors with a dual binding motif in the International Journal of Molecular Sciences (3.5.2016, in German).
- ZHAW News Release / on cover story about the de novo design and synthesis of protease inhibitors based on natural product fragments in ChemMedChem (11.3.2015, in German).
- Strukturbasiertes Wirkstoffdesign(PDF 1,5 MB) (ChemiePlus 4/14, German)
- Fighting the resistance(PDF 85,2 KB) (Pan European Networks Horizon 2020 Projects Portal 4/14)
- Strategic Targeting of Multiple Water-Mediated Interactions: A Concise and Rational Structure-Based Design Approach to Potent and Selective MMP-13 Inhibitors (ChemMedChem 2013)
- Bridging the disciplines(PDF 110,3 KB) (Pan European Networks: Science & Technology 7/2013)
- Zielgerichtete Medikamente(PDF 1,3 MB) (Impact 3/13, German)
- International Innovation Report(PDF 2,5 MB) (Interview and Report in International Innovation, 1/2013)
- chemf: A purely functional chemistry toolkit (highly accessed, 20.12.12)
- Rückblick auf den Chemie-Tag mit dem Thema Medizinalchemie(PDF 51,8 KB) (3. Wädenswiler Chemie-Tag, 2011, German)
- Im Kampf gegen resistente Keime (20min Online, 15.05.11, German)
- Wirkstoffdesign: Ein Molekül gegen Krebs(PDF 156,9 KB) (Impact 7/09, German)
- Design and synthesis of novel scaffolds for therapeutically validated drug targets(PDF 169,8 KB) (Master Theses)
