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SLAS2020 Short Courses

Applications of Biophysical Methods in Small-Molecule Drug Discovery

The course will be delivered in two sections. The first section will focus on the theoretical aspects of each biophysical method in a seminar format and the second will focus on their practical applications via an open and active discussion format.

In the first section attendees will receive a series of brief high-level presentations concerning the biophysical theory behind each technology and their application in lead finding and hit validation, as well as include more in-depth mechanistic studies. This will enable learners to gain a rapid overview of the most relevant biophysics and label-free technologies for screening and lead finding and characterization.

In the second section, learners will be presented with challenges on how to effectively apply those technologies by looking at a range of common scenarios from different phases of lead discovery. This will include fragment-based drug discovery, hit validation and confirmation, in-depth hit characterization and support of HTS assay development. Making use of an active and open discussion forum, teams will thereby gain further insight about the usage, impact and limitations of each biophysical technology.

Who Should Attend?

  • People interested in getting an overview about the current toolbox of affinity-based, biophysical methods currently applied in drug discovery.
  • Biophysical technology experts who want to learn more about other orthogonal approaches.
  • Project leaders who want to understand which technologies suit their needs and how to correctly place in chemical lead characterization.
  • Medicinal chemists who want to learn more about the generation of biophysical data used in drug design.
  • Technology providers who want to gain more insight into the needs of typical users and the limitations they experience.

Course Benefits

  • Get a broad overview about what’s new art in the field.
  • Comprehend which technology best fits into individual project needs and scientific questions.
  • Learn about typical applications and "best practices" as well as limitations and practical considerations.
  • Understand how the biophysics technologies relate to each other and how they augment and synergize with data from other approaches.
  • Be able to predict which technology (or combinations thereof) serves best in typical drug discovery flowchart placement.

Course Topics

  • Overview of the most relevant biochemical biophysics and label-free technologies for screening and lead finding.
  • Main technologies discussed in more detail: Mass Spectrometry; NMR; Calorimetry (DSC, ITC); SPR; Interferometry; Resonance Waveguide Grating (aka Corning Epic); thermal protein denaturation and aggregation assays (DSF aka Thermofluor, DSLS aka Stargazer, CETSA; nanoDSF) and Dynamic Light Scattering; Microscale Thermophoresis (NanoTemper).
  • Understand which technology combinations best solve specific drug discovery process needs.
  • Grasp how biophysics can support assay development for screening and how biophysical data can be used to fuel medicinal chemistry design.

Course Pre-Reading Requirements

General introduction into affinity-based methods and their application in Drug Discovery:
(articles which describe how the approaches work, caveats, and a summary of their impact)

  1. Integrating biophysics with HTS-driven drug discovery projects
    Folmer, Rutger H.A.
    Drug Discovery Today, March 2016, Vol.21(3), pp.491-498
    Identifier: ISSN: 1359-6446 ; DOI: 10.1016/j.drudis.2016.01.011
  2. Applications of Biophysics in High-Throughput Screening Hit Validation
    Genick, Christine Clougherty ; Barlier, Danielle ; Monna, Dominique ; Brunner, Reto ; Bé, Céline ; Scheufler, Clemens ; Ottl, Johannes
    Journal of biomolecular screening, June 2014, Vol.19(5), pp.707-14
    Identifier: E-ISSN: 1552-454X ; PMID: 24695619 Version:1 ; DOI: 10.1177/1087057114529462
  3. Biophysics in Drug Discovery: impact, challenges, and opportunities,
    Jean-Paul Renaud, Chun wa Chung, U. Helena Danielson, Ursula Egner, Michael Hennig, Roderick E. Hubbard, and Herbert Nar
    Nature Reviews, August 2016, Vol.15(10), pp. 679-98
    DOI: 10.1038/nrd.2016.123

Background Information on each technology/approach:

  • DLS:
    Making sense of Brownian motion: colloid characterization by dynamic light scattering
    Hassan, Puthusserickal A ; Rana, Suman ; Verma, Gunjan
    Langmuir : the ACS journal of surfaces and colloids, 13 January 2015, Vol.31(1), pp.3-12
    Identifier: E-ISSN: 1520-5827 ; PMID: 25050712 Version:1 DOI: 10.1021/la501789z
  • TSA:
    Thermal denaturation assays in chemical biology
    Senisterra, Guillermo ; Chau, Irene ; Vedadi, Masoud
    Assay and drug development technologies, April 2012, Vol.10(2), pp.128-36
    Identifier: E-ISSN: 1557-8127 ; PMID: 22066913 Version:1 DOI: 10.1089/adt.2011.0390
  • CETSA:
    The cellular thermal shift assay for evaluating drug target interactions in cells
    Jafari, Rozbeh ; Almqvist, Helena ; Axelsson, Hanna ; Ignatushchenko, Marina ; Lundbäck, Thomas ; Nordlund, Pär ; Martinez Molina, Daniel
    Nature protocols, September 2014, Vol.9(9), pp.2100-22
    Identifier: E-ISSN: 1750-2799 ; PMID: 25101824 Version:1 DOI: 10.1038/nprot.2014.138
  • MST:
    Microscale Thermophoresis: Interaction analysis and beyond
    Jerabek-Willemsen, Moran ; André, Timon ; Wanner, Randy ; Roth, Heide Marie ; Duhr, Stefan ; Baaske, Philipp ; Breitsprecher, Dennis
    Journal of Molecular Structure, 5 December 2014, Vol.1077, pp.101-113
    Identifier: ISSN: 0022-2860 ; DOI: 10.1016/j.molstruc.2014.03.009
  • MS:
    Affinity selection-mass spectrometry screening techniques for small molecule drug discovery
    Annis, D. Allen ; Nickbarg, Elliot ; Yang, Xianshu ; Ziebell, Michael R. ; Whitehurst, Charles E.
    Current Opinion in Chemical Biology, 2007, Vol.11(5), pp.518-526
  • NMR:
    Parallel screening of low molecular weight fragment libraries: do differences in methodology affect hit identification?
    Wielens, Jerome ; Headey, Stephen J ; Rhodes, David I ; Mulder, Roger J ; Dolezal, Olan ; Deadman, John J ; Newman, Janet ; Chalmers, David K ; Parker, Michael W ; Peat, Thomas S ; Scanlon, Martin J
    Journal of biomolecular screening, February 2013, Vol.18(2), pp.147-59
    Identifier: E-ISSN: 1552-454X ; PMID: 23139382 Version:1 DOI: 10.1177/1087057112465979
  • SPR:
    Biomolecular interaction analysis in drug discovery using surface plasmon resonance technology
    Huber, W ; Mueller, F
    Current Pharmaceutical Design, 2006, Vol.12(31), pp.3999-4021
    Identifier: ISSN: 1381-6128
  • RWG:
    Resonant waveguide grating for monitoring biomolecular interactions
    Wu, Meng ; Li, Min
    Methods in molecular biology (Clifton, N.J.), 2015, Vol.1278, pp.139-52
    Identifier: E-ISSN: 1940-6029 ; PMID: 25859947 Version:1 ; DOI: 10.1007/978-1-4939-2425-7_8
  • ITC:
    Direct measurement of protein binding energetics by isothermal titration calorimetry
    Leavitt, Stephanie ; Freire, Ernesto
    Current Opinion in Structural Biology, 2001, Vol.11(5), pp.560-566
    Identifier: ISSN: 0959-440X ; DOI: 10.1016/S0959-440X(00)00248-7
  • Xray:
    Effective and Emerging Strategies for utilizing Structure in Drug Discovery
    Brown, Ka ; Davenport, R ; Ward, Se
    Drugs Of The Future, 2015 Apr, Vol.40(4), pp.251-256 [Peer Reviewed Journal]
    Identifier: ISSN: 0377-8282 ; DOI: 10.1358/dof.2015.040.04.2314768

Instructors

Christian Bergsdorf

Christian Bergsdorf, Ph.D.
Novartis Institutes for BioMedical Research Basel, Chemical Biology and Therapeutics; Protein Sciences

Since 1999, Christian Bergsdorf, Ph.D. has been working in the academic, biotech and big pharma research institutes, focusing on mechanistic protein characterization and development and implementation of new biochemical and biophysical assay techniques in the early lead discovery process. In 2008, he joined the Biophysics group in Novartis Basel as a laboratory head. In this role, he applied and tailored biophysical methods for their usage in early lead finding, validation and MoA studies to get a deeper understanding about target-ligand interactions. He also evaluated and implemented new biophysical approaches in early lead discovery to enable higher throughput biophysics and to tackle difficult targets as membrane proteins, protein complexes and nucleic acids.

Geoff Holdgate

Geoff Holdgate
AstraZeneca R&D UK, Discovery Sciences, HTS

Geoff joined ICI as a member of the Protein Function Team in 1992. ICI Pharmaceuticals subsequently became Zeneca Pharmaceuticals, which merged with Astra to form AstraZeneca. During the last 26 years Geoff has applied the techniques associated with mechanistic enzymology and biophysics to the study of structure-function relationships on numerous drug targets and associated ligands, including several successful projects producing marketed drugs. As Principal Scientist in Biophysics, over the last 15 years, he has applied biophysical methods to facilitate the mechanistic characterisation of protein-ligand interactions and to enable fragment-based lead generation approaches. He has had a shared responsibility for, and an excellent track record of, developing and implementing new biophysical approaches to aid early lead finding activities. He has recently taken up the position of Associate Director in High-throughput Screening at AstraZeneca, where he will continue to promote the use of biophysical methods for identifying, evaluating and characterising hits and leads.


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