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Technische Universität München Natural Products and Derivatives As Technische Universität München Fakultät für Chemie Bayerisches NMR Zentrum Lehrstuhl für Biomolekulare NMR-Spektroskopie Natural products and derivatives as novel scaffolds targeting PTP1B Eleni Kyriakou Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Prof. Dr. Franz Hagn Prüfer der Dissertation: 1. Prof. Dr. Michael Sattler 2. Prof. Dr. Dierk Niessing Die Dissertation wurde am 18.10.2017 bei der Technischen Universität München eingereicht und durch die Fakultät für Chemie am 04.12.2017 angenommen. II Table of Contents Abstract ............................................................................................................................... 1 1. Introduction I: Biological background ....................................................................... 5 1.1 Diabetes mellitus type 2 ............................................................................................. 5 1.2 Protein Tyrosine Phosphatases (PTPs) ...................................................................... 6 1.3 PTP1B structural characteristics ................................................................................ 8 1.4 PTP1B reaction mechanism ....................................................................................... 9 1.5 Role of PTP1B in insulin and leptin regulation ....................................................... 10 1.6 PTP1B as drug target ............................................................................................... 11 1.7 PTP1B inhibitors for the treatment of T2D ............................................................. 12 1.7.1 Active site inhibitors ................................................................................................ 12 1.7.2 Allosteric inhibitors ................................................................................................. 21 1.7.3 Others compounds ................................................................................................... 23 1.8 TCPTP...................................................................................................................... 24 2. Introduction II: NMR Spectroscopy ......................................................................... 28 2.1 NMR Spectroscopy .................................................................................................. 28 2.1.1 NMR Spectroscopy Principles ................................................................................. 28 2.1.2 Product operator formalism ..................................................................................... 31 2.1.3 Relaxation ................................................................................................................ 33 2.1.4 NMR experiments for backbone protein assignment ............................................... 33 2.2 NMR approaches in SBDD ...................................................................................... 39 2.2.1 Protein-based NMR methods ................................................................................... 39 2.2.2 Ligand-based NMR methods ................................................................................... 40 Scope of the thesis ............................................................................................................. 44 III 3. Material and methods ................................................................................................ 46 3.1 Materials .................................................................................................................. 46 3.1.1 List of materials ....................................................................................................... 46 3.1.2 Instrumentation ........................................................................................................ 49 3.1.3 Cell strains ............................................................................................................... 50 3.1.4 Genes........................................................................................................................ 50 3.1.5 Buffers and expression media protocols .................................................................. 51 3.2 Methods.................................................................................................................... 56 3.2.1 Cloning ..................................................................................................................... 56 3.2.2 DNA purification by agarose gel electrophoresis .................................................... 58 3.2.3 Competent cells transformation ............................................................................... 58 3.2.4 Mini-Preps and DNA sequencing ............................................................................ 58 3.2.5 Protein overexpression ............................................................................................. 59 3.2.6 Protein purification .................................................................................................. 60 3.2.7 Protein Detection and Evaluation ............................................................................ 62 3.2.8 In vitro assays .......................................................................................................... 64 3.2.9 SwitchSENSE .......................................................................................................... 75 3.2.10 Cell assay ................................................................................................................. 76 3.3 In silico studies with HADDOCK ........................................................................... 77 4. Results I: Challenges and solutions for recombinant PTPs protein expression, purification and evaluation .............................................................................................. 78 4.1 Constructs ................................................................................................................ 78 4.2 Protein expression and purification ......................................................................... 80 4.2.1 Strain selection ......................................................................................................... 80 4.2.2 Medium selection for unlabeled protein production ................................................ 80 IV 2 15 13 4.2.3 Isotope labeled protein ( H/ N/ C) ........................................................................ 81 4.2.4 Protein purification .................................................................................................. 82 4.3 In vitro assays .......................................................................................................... 83 4.3.1 Thermofluor screening of PTP1B1-321 ...................................................................... 83 4.3.2 Protein NMR spectroscopy ...................................................................................... 84 4.3.3 Phosphatase activity assay ....................................................................................... 86 5. Results II: Novel scaffolds modulating potently PTP1B and TCPTP activity ..... 90 5.1 Compound Library ................................................................................................... 90 5.1.1 Triterpenoids ............................................................................................................ 91 5.1.2 Steroids, Sterols and Secosteroids ......................................................................... 100 5.1.3 Other compounds ................................................................................................... 112 5.2 Thermofluor screening ........................................................................................... 117 5.3 Crystallization of PTP1B1-321 with compounds ..................................................... 119 5.4 Cell assay ............................................................................................................... 123 6. Results III: Celastrol reverses obesity by inhibiting PTP1B and TCPTP .......... 128 6.1 Activity assay with celastrol .................................................................................. 128 6.2 Mapping of the celastrol binding site by NMR Spectroscopy ............................... 129 6.3 In silico studies with Haddock ............................................................................... 133 6.4 Cell assay with celastrol......................................................................................... 134 6.5 Withaferin A .......................................................................................................... 136 6.6 Celastrol reactivity ................................................................................................. 137 6.7 Activity assay ......................................................................................................... 142 6.8 NMR studies .......................................................................................................... 144 6.9 MALDI-TOF analysis ............................................................................................ 146 6.10 SOCS3 protein ....................................................................................................... 147 V 6.11 SwitchSENCE .......................................................................................................
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