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Reducing Attrition Via Improved Strategies for Pre Till Mor och Far List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Elinder, M., Geitmann, M., Gossas, T., Källblad, P., Winquist, J., Nordström, H., Hämäläinen, M., and Danielson, UH. (2011) Experimental validation of a fragment library for lead discovery using SPR biosensor technology. Journal of Biomolecular Screening. 16(1):15-25 II Winquist, J., Nordström, H., Geitmann, M., Gossas, T., Ho- man, E., Hämäläinen, M., and Danielson, UH. New Scaffolds for Design of Inhibitors of Drug Resistant HIV-1 Protease Iden- tified by Fragment Library Screening. Submitted. III Winquist, J., Abdurakhmanov, E., Baraznenok, V., Henderson, I., Vrang, L., and Danielson, UH. Resolution of the Interaction Mechanisms and Characteristics of Non-nucleoside Inhibitors of Hepatitis C Virus Polymerase – Laying the Foundation for Discovery of Allosteric HCV Drugs. Submitted. IV Winquist, J., Gustafsson, L., Nilsson, I., Musil, D., Deinum, J., Geschwindner, S., Xue, Y., and Danielson, UH. Identification of structure-kinetic and structure-thermodynamic relationships for thrombin inhibitors. Manuscript. Reprints were made with permission from the respective publishers. Contents Introduction ................................................................................................... 11 Drug discovery ......................................................................................... 11 Attrition – a costly problem ................................................................. 11 Phases of pre-clinical drug discovery .................................................. 12 Clinical trials ........................................................................................ 13 Levels of therapeutic intervention ............................................................ 13 Enzymes as drug targets ...................................................................... 14 Proteases ......................................................................................... 14 Polymerases .................................................................................... 15 RNA viruses – a moving target ................................................................ 15 Human immunodeficiency virus, HIV................................................. 16 Therapies ......................................................................................... 16 Taxonomy and molecular virology ................................................. 17 HIV-1 protease ................................................................................ 17 Hepatitis C virus, HCV ........................................................................ 18 Therapies ......................................................................................... 18 Taxonomy and molecular virology ................................................. 19 HCV polymerase, NS5B ................................................................. 20 Endogenous targets .................................................................................. 21 Cardiovascular diseases ....................................................................... 21 Thrombin ......................................................................................... 21 Physicochemical properties of drugs ........................................................ 22 Fragment-based drug discovery, FBDD ................................................... 23 General approaches for drug discovery .................................................... 25 Metrics in drug discovery ......................................................................... 26 Interaction analysis ................................................................................... 27 Affinity, kinetics, and interaction mechanisms ................................... 27 Thermodynamic interaction analysis ................................................... 29 Techniques for interaction analysis ..................................................... 32 Surface plasmon resonance-based biosensors ................................. 32 Aims .............................................................................................................. 36 Present investigations .................................................................................... 37 Paper I – Design and validation of a fragment library ............................. 37 Interaction profiles ............................................................................... 37 Fragments with slow dissociation rates ............................................... 38 Superstoichiometry may be an insidious and non-general trait ........... 38 Conclusions ......................................................................................... 38 Paper II – Screening for novel enzyme inhibitor scaffolds ...................... 39 Tversky coefficient as a measure of similarity .................................... 41 Conclusions ......................................................................................... 41 Logistical challenges in compound screening (Papers I and II) .............. 42 Paper III – Cellular potency, mechanism, and kinetics of allosteric enzyme inhibitors ..................................................................................... 43 Assessment of interaction mechanism ................................................. 44 Chemo- and thermodynamic evaluation of interactions ...................... 44 Inhibitor interference of NS5BΔ21 RNA-binding ............................... 46 Conclusions ......................................................................................... 46 Paper IV – Structure-kinetic and -thermodynamic relationships of enzyme inhibitors ..................................................................................... 47 Conclusions ......................................................................................... 48 Perspectives .................................................................................................. 49 Summary .................................................................................................. 49 Future studies ........................................................................................... 50 Notes ............................................................................................................. 51 Computer software for visualization ........................................................ 51 Sammanfattning på svenska (Summary in Swedish) ................................... 52 Bakgrund och målsättning ........................................................................ 52 Delarbeten ................................................................................................ 53 Slutsatser .................................................................................................. 53 Acknowledgements ....................................................................................... 54 References ..................................................................................................... 56 Abbreviations CD Candidate drug DMSO Dimethyl sulfoxide DSF Differential scanning fluorometry DTT Dithiothreitol EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydro chloride FBDD Fragment-based drug discovery FDA US Food and Drug Administration FRET Förster resonance energy transfer GPCR G-protein-coupled receptor HCV Hepatitis C virus HIV Human immunodeficiency virus HTS High throughput screening IRES Internal ribosomal entry site ITC Isothermal titration calorimetry MS Mass spectrometry NHS N-hydroxysuccinimide NME New molecular entity NMR Nuclear magnetic resonance NS Non-structural protein NTP Nucleoside triphosphate OGP n-octyl-β-D-glucopyranoside PCR Polymerase chain reaction PD Pharmacodynamic PDB ID Protein Data Bank identity PK Pharmacokinetic R&D Research and development RT Reverse transcriptase SAR Structure-activity relationship SF Stopped-flow spectroscopy SKR Structure-kinetic relationship SPR Surface plasmon resonance v/v Volume to volume ratio Introduction Drug discovery Drug discovery is a complex, multivariate process aiming at designing a stable, potent compound with high therapeutic efficacy and low toxicity. Furthermore, production of the compound should be chemically and eco- nomically tractable. All of these aspects are affected by the structural and physicochemical properties of the compound, established in the pre-clinical phase of drug discovery. This thesis has the overall aim to reduce attrition in drug discovery via two interim aims. The first is to better understand what strategies are effi- cient for drug discovery. In order to ultimately reach compounds efficient in clinic, the second has been to develop methods to extract information valua- ble when prioritizing and optimizing substances during the development process. Attrition – a costly problem The number of new molecular entities (NME) approved by the US Food and Drug Administration (FDA) were <1 per company annually for nine of the largest pharmaceutical companies during the period 2005-2010. With a con- tinuous increase in R&D spending during the same period, the annual amount had by the end of 2010 reached 60 billion US dollars [1]. The cost to develop a drug from a screening hit to a compound approved for clinical use has been estimated to approximately US$ 1.8 billion [2]. In each step of the drug discovery process, many potential drugs are ex- cluded. In the early 1990´s
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