Recent improvements in biophysical techniques have enabled higher throughput applications and fueled progress in fields such as PPI and Fragment-Based Drug Discovery. CHI’s new one-day symposium will be a mix of short introductory talks, in-depth case studies and discussions about the most current biophysical techniques. The focus will be on when and how to use which method. The symposium should be of interest to: biophysicists seeking to expand beyond their specialty in order to participate in ‘strategic’ project management, medicinal chemists involved in choosing which techniques best serve a project’s needs, computational chemists and discovery biologists.
Final Agenda
8:00 am Registration and Morning Coffee
8:30 Chairperson’s Opening Remarks
Chris Smith, Ph.D., Director, Medicinal Chemistry, COI Pharmaceuticals
8:40 FEATURED PRESENTATION: Application of Label-free Biosensors in Drug Discovery: The Past, Present and Future
John Quinn, Ph.D., Director, Structural and Biophysical Chemistry, Genentech
Label-free biosensing enables a diverse range of information rich functional assays informing the entire drug discovery-development process. A low barrier to ownership and seemingly intuitive operation have contributed to the success of the technology. However label-free biosensing is not a “turn-key” technology as practitioners must optimize methodologies and data analysis protocols for each affinity system of interest. What are the components of a successful label-free biosensing group? What are the current capabilities and limits? What does the future hold? To address these questions we provide a brief historical overview of the technology and then review high impact applications with emphasis on practical strengths and limitations. We conclude with perspectives on the future direction of the technology.
9:25 Commitment to Covalency: Using SPR to Understand and Evaluate the Potency of Highly Optimized Irreversible Inhibitors
Phillip Schwartz, Ph.D., Senior Scientist, Biophysical Chemistry, Takeda California
Kinetic analysis of potent, highly optimized irreversible inhibitors is a complex prospect. This work presents an approach for the understanding and evaluation of optimized irreversible inhibitor potency and identifies the key parameters that should be used to characterize them. The practical considerations that arise from these inhibitors are discussed. Among these are methods to assess potency, SAR optimization strategies and the impact on pharmacokinetics/pharmacodynamics.
9:55 Coffee Break in the Exhibit Hall with Poster Viewing
10:35 Nuclear Magnetic Resonance (NMR) Spectroscopy in Pharma Today: We’ve Got an App for That
Mary Harner, Ph.D., Research Investigator, Mechanistic Biochemistry, Bristol Myers-Squibb
NMR spectroscopy has been demonstrated as a powerful tool in drug discovery for structure determination and the detection of ligand binding events. The flexibility of NMR can be harnessed to address challenging questions and systems by finding the proper balance of its applications. Approaches will be described to accelerate data acquisition and analysis to enable NMR to remain an essential tool among biophysical technologies.
11:05 Medium to High-Throughput Methods for Biophysical Profiling of Compounds during Drug Discovery
Rumin Zhang, Ph.D., Senior Principal Scientist, in vitro Pharmacology, Merck Research Laboratories
We share our best practices in various biophysical profiling methods including automated stopped flow, global progress curve analysis, biosensors, mass spectrometry and thermal shift assays. These methods cover up to nine orders of kinetic time frame from milliseconds to days. They also cover nine orders of magnitude in thermodynamic potency measurement. The audience should gain both, the breadth and depth of our biophysical profiling methods, as well as valuable best practices employed in our labs.
11:35 Panel Discussion: Finding Hits without HTS
Moderator:
Chris Smith, Ph.D., Director, Medicinal Chemistry, COI Pharmaceuticals
An HTS screen continues to dominate as the preferred method of choice to find hits for novel small molecule drug discovery projects by pharma and venture backed biotechs. The panel will lead a discussion to examine alternative approaches to HTS for hit generation. We will discuss Fragment, Encoded and Virtual/Focused Library Screening. Check the website for specific discussion points.
Panelists: Ben Davis, Ph.D., Research Fellow, Biology, Vernalis Resesarch; Mary Harner, Ph.D., Research Investigator, Mechanistic Biochemistry, Bristol Myers-Squibb; Christopher Phelps, Ph.D., Manager, Drug Design& Selection, Boston RD Platform Technology & Science, GSK
- Fragment Library Screening
- How is more chemical space screened by screening fewer compounds?
- What about the issue of detection? The issue of false positives?
- Can the case be made for fragment screening is an alternative to HTS?
- Encoded Library Screening
- Can the case be made for encoded library screening as an alternative to HTS
- Virtual Library Screening / Focused Library Screening
- Hit rate enrichment facilitating medium throughout screening
12:05 pm Sponsored Presentation (Opportunity Available)
12:20 Enjoy Lunch on Your Own
1:35 Chairperson’s Remarks
Yongchao Su, Ph.D., Senior Scientist, Pharmaceutical Sciences & Clinical Supply, Merck Research Laboratories
1:40 The Structure-Function Relationship of Membrane Proteins using Solid-State NMR Spectroscopy
Yongchao Su, Ph.D., Senior Scientist, Pharmaceutical Sciences & Clinical Supply, Merck Research Laboratories
I describe using solid state NMR (ssNMR) to investigate the atomic-level structures of insoluble and pharmaceutically important bio-macromolecules, and correlate to their biological functions. A few interesting membrane-active proteins, peptides and drug molecules, including cell-penetrating peptides (CPPs), antimicrobial peptides (AMPs), antimicrobial drugs (AMDs), and ion channels (gating helix of K+ channel, transmembrane 1H channel of influenza M2 protein, voltage-dependent anion channel), will be included.
2:10 GPCR Studies with Nuclear Magnetic Resonance: Challenges and Advances
Matthew Eddy, Ph.D., Postdoctoral Fellow, Ray Stevens Laboratory, The Bridge Institute, University of Southern California
To understand the function of G Protein-Coupled Receptors (GPCRs), deeper insight is needed into the role of conformational dynamics in molecular recognition and activation. Nuclear magnetic resonance (NMR) is uniquely suited to deliver information about dynamics at atomic resolution and over a large range of time scales. However, application of NMR to study GPCRs has so far been very challenging. I will present advances in the field that address some of these challenges and reveal initial insights into mechanisms of GPCR activation.
2:40 Liposome-Protein Binding Assays based on Bio-Layer Interferometry
Jakob Wallner, Ph.D., Research Scientist, Department of Biotechnology, University of Natural Resources and Life Sciences, Vienna
Due to the attractiveness of biosensor based methods, there is a growing need for more efficient, more simple and reliable methods for the intended purpose. Based on Fortebio’s BLI platform we are establishing different assays to study protein/liposome interactions in more detail. The selected examples address assay development for the liposome approach, the use of different sensor types and individual protein aspects. Individual assays emphasis the binding kinetics of liposomes with different protein classes such as enzymes, antibodies and hormones.
3:10 Refreshment Break in the Exhibit Hall with Poster Viewing
3:40 A Mass-Spectrometry platform for Discovery and Characterization of Modulators of Histone Post-Translational Modifications
Andrew Andrews, Ph.D., Assistant Professor, Cancer Genetics, Fox Chase Cancer Center
Previously, little was known about the residue specificity of histone modifying enzymes because standard assays either quantitate or determine the location of modification. We have developed a high/medium throughput label-free quantitative mass spectrometry assay that can provide both of these pieces of data, from any source. Furthermore, we demonstrate the ability of small molecules to alter the selectivity of these enzymes, suggesting the ability to pharmacology alter histone modification patterns and disease outcomes.
4:10 Drug Discovery at the Single Molecule Level
Tim Kaminski, Ph.D., Postdoctoral Fellow, Biophysics/Discovery Sciences, AstraZeneca
I present a toolbox we are developing to advance single molecule microscopy from a method primarily used in academia into a versatile tool for drug discovery. We aim to address shortcomings of established biophysical methods such as tight binding limit, working with membrane proteins and higher throughput. Additionally we are able to extract kinetic profiling of inhibition reactions in solution by observing the association and dissociation of thousands of molecules in parallel with a surface-based single molecule platform.
4:40 Close of Symposium