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Fragment-Based Drug Discovery Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1999 Fragment-based drug discovery Novel methods and strategies for identifying and evolving fragment leads EDWARD A. FITZGERALD ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-513-1106-7 UPPSALA urn:nbn:se:uu:diva-429950 2021 Dissertation presented at Uppsala University to be publicly examined in A1:107a, BMC (Biomedicinsk Centrum), Husargatan 3, Uppsala, Wednesday, 24 February 2021 at 09:15 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Professor Hanna-Kirsti Schrøder Leiros (UiT The Arctic University of Norway). Abstract FitzGerald, E. A. 2021. Fragment-based drug discovery. Novel methods and strategies for identifying and evolving fragment leads. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1999. 59 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-1106-7. The need for new drugs became ever more apparent in the year 2020 when the world was faced with a viral pandemic. How drugs are discovered and their relevance to society became part of daily discussions in workplaces and homes throughout the world. Consequently, efficient strategies for preclinical drug discovery are clearly needed. The aim of this thesis has been to contribute to the drug discovery process by developing novel methods for fragment-based drug discovery (FBDD), a rapidly developing approach where success relies on access to sensitive and informative analytical methods as well as chemical compounds with suitable properties. This process is fundamentally dependent on the interplay between scientists and engineers across biology, chemistry and physics. This project is characterized by the development and implementation of novel biophysical methods over a series of studies, which are subdivided into: 1. Development of biosensor assays and approaches for challenging targets, 2. Discovery of fragments targeting dynamic proteins using biosensors, and 3. Reconstruction of ligands using fragment-based strategies. A selection of diverse targets was used as challenging prototypes for the target agnostic methodologies described herein. The targets in focus were: acetylcholine-binding protein (AChBP), a soluble homologue of ligand gated ion channels, and two complex multi-domain epigenetic enzymes lysine specific demethylase 1 (LSD1) and SET and MYND domain- containing protein 3 (SMYD3). Expression, purification, engineering of protein variants, and biochemical characterization were required before robust screening strategies could be established. Three types of biosensors, based on different time-resolved and very sensitive detection principles (SPR, SHG, GCI), were used to identify and characterize the kinetics of the interactions of novel fragments for the proteins. For SPR, a variety of multiplexed assays were designed for the screening of fragments against difficult targets. Notably, it led to the identification of an allosteric ligand and site in SMYD3, which was subsequently characterized kinetically and structurally using X-ray crystallography, and further evolved using computational approaches. An innovative SHG assay for the specific detection of ligands inducing conformational changes was developed and used for fragment screening against AChBP. It revealed that fragments with a potential to serve as functional regulators of ligand gated ion channels can be identified using this technique. The combined application of the novel biophysical and computational approaches enabled the identification of useful starting points for drug discovery projects. Keywords: Biochemistry, Drug Discovery, Biophysics, Fragment-based drug discovery, Epigenetics, Biosensors, Surface Plasmon Resonance, Interaction Analysis, Second- Harmonics Edward A. FitzGerald, Department of Chemistry - BMC, Biochemistry, Box 576, Uppsala University, SE-75123 Uppsala, Sweden. © Edward A. FitzGerald 2021 ISSN 1651-6214 ISBN 978-91-513-1106-7 urn:nbn:se:uu:diva-429950 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-429950) List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I FitzGerald, E.A., Vagrys, D., Opassi, G., Klein, H.F., Hamilton, D.J., Boronat, P., Cederfelt, D., Talibov, V.O., Abramsson, M., Moberg, A., Lindgren, M.T., Holmgren, C., Dobritzsch, D., Da- vis, B., O’Brien, P., Wijtmans, M., van Muijlwijk-Koezen, J.E., Hubbard, R.E., de Esch, I.J.P., Danielson, U.H. (2020) Multi- plexed experimental strategies for fragment library screening us- ing SPR biosensors. bioRxiv, doi: 10.1101/2020.12.23.424167. II FitzGerald, E.A., Butko, M., Boronat, P., Cederfelt, D., Abramsson, M., Ludviksdottir, H., van Muijlwijk-Koezen, J.E., de Esch, I.J.P., Dobritzsch, D., Young, T., Danielson, U.H. (2020) Discovery of fragments targeting dynamic proteins using second-harmonic generation. Submitted III Talibov, V.O., Fabini, E., FitzGerald, E.A., Tedesco, D., Cederfelt, D., Talu, M.J., Rachman, M.M., Mihalic, F., Manoni, E., Naldi, M., Sanese, P., Forte, G., Signorile, M.L., Barril, X., Simone, C., Bartolini, M., Dobritzsch, D., Del Rio, A., Dan- ielson, U.H. (2021) Discovery of allosteric ligand binding site in SMYD3 lysine methyltransferase. ChemBioChem, Accepted Au- thor Manuscript. doi: 10.1002/cbic.202000736. IV FitzGerald, E.A., Rachman, M.M., Cederfelt, D., Zhang, H., Barril, X., Dobritzsch, D., Koehler, K., Danielson, U.H. (2021) Evolution of an allosteric ligand of the epigenetic modulator SMYD3 - Retrosynthesis using an integrated biophysical and computational approach. Manuscript Reprints were made with permission from the respective publishers. Contribution report Paper I Planned the study. Produced and purified AChBP and LSD1. Designed and performed kinetic experiments, designed and performed thermal shift assays, screened initial crystallog- raphy conditions. Analysed data from these experiments. Co- wrote the manuscript. Paper II Planned the study. Produced and purified AChBP, designed single cysteine mutants and conducted site directed mutagen- esis. Developed and performed SHG experiments, analysed the data. Developed and performed grating-coupled interfer- ometry assay, analysed data. Wrote the manuscript. Paper III Participated in planning of the study, performed computa- tional experiments and analysed SMYD3 surface features, contributed to writing the manuscript. Paper IV Planned the study. Produced and purified SMYD3. Partici- pated in the design of compounds, acquired compounds. De- veloped grating-coupled interferometry assay, performed ex- periments and analysed data. Set crystals. Wrote the manu- script. Contents Introduction ................................................................................................. 9 Drug discovery ....................................................................................... 9 Early stage & preclinical drug discovery ............................................. 10 Phases of preclinical drug discovery ............................................... 11 High-throughput screening .............................................................. 11 Fragment-based drug discovery ....................................................... 12 An interdisciplinary and highly collaborative effort ....................... 15 Molecular recognition in drug discovery .................................................. 16 Functional interactions beyond binding ............................................... 19 Protein-protein interactions ............................................................. 19 Analysis of biomolecular interactions using label-free biosensor-based methods ................................................................................................ 20 Surface Plasmon Resonance (SPR) ................................................. 21 Grating Coupled Interferometry (GCI) ............................................ 21 Analysing kinetic data with label-free biosensor-based methods ........ 23 Interaction mechanisms ........................................................................ 24 1:1 (Langmuir) binding model ........................................................ 24 Heterogenous ligand model ............................................................. 24 Steady-state affinity ......................................................................... 25 Analysis of biomolecular interactions using labelled biosensor-based methods ................................................................................................ 25 Second-Harmonic Generation (SHG) .............................................. 26 Orthogonal validation and structural insights ...................................... 26 Protein crystallography .................................................................... 27 Computational methods ................................................................... 27 Aim ........................................................................................................... 29 Present investigation ................................................................................. 30 Target proteins ...................................................................................... 31 Compound libraries .............................................................................. 32 Discovery of fragment hits (Papers I & II) .......................................... 33 Improving SPR biosensor-based
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