Cambridge Healthtech Institute’s 4th Annual
Biophysical Approaches for Drug Discovery
New Methods and Lead Generation Strategies for Medicinal Chemists
April 12, 2019 | Hard Rock Hotel | San Diego, California
Recent advances in automation and sensitivity of biophysical approaches for measuring biomolecules interacting with one another has spurred progress in drug discovery. Technologies such as nuclear magnetic resonance (NMR), surface plasmon resonance (SPR),
other biosensor-based assays, isothermal titration calorimetry (ITC), and thermal shift assays (TSAs) have enabled discovery of compounds targeting protein-protein interactions and complex membrane protein targets. These target classes are more difficult
to ‘drug’ because they are either harder to solubilize or not as amenable as are traditional intracellular enzyme targets to in-vitro-based, biochemical functional assays for high throughput screening. Fragment-based drug design is also
another lead generation approach that is very dependent on biophysical technologies. Cambridge Healthtech Institute's 4th Annual Biophysical Approaches for Drug Discovery symposium will bring together medicinal chemists, structural
biologists, biophysical chemists and computational researchers to discuss the latest biophysical advances and see examples and discuss strategies for when to apply them for more efficient drug lead generation.
Final Agenda
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Friday, April 12
7:30 am Registration Open and Morning Coffee
7:55 Welcome and Opening Remarks
Anjani Shah, PhD, Senior Conference Director, Cambridge Healthtech Institute
Seungil Han, PhD, Associate Research Fellow, Structure Biology & Biophysics, Pfizer Global R&D
8:00 FEATURED PRESENTATION: Characterization of Novel STING Ligands Using SPR and Orthogonal Approaches
Gottfried Schroeder, PhD, Senior Scientist, Department of Pharmacology, Merck Research Labs - Boston
Modulation of the innate immune receptor STING is of pharmacological interest for both oncology and autoimmune indications. Binding of cyclic dinucleotide 2’3’-cGAMP to dimeric STING stabilizes a ‘lid-closed’ protein conformation,
ultimately inducing interferon production. Biophysical characterization of different classes of STING ligands using surface plasmon resonance (SPR) has revealed significant differences in binding kinetics, stoichiometry and mode of action.
The results of complimentary techniques further support these observed mechanistic differences.
8:30 Advanced Biophysical Methods for Driving Lead Generation in the Right Direction
Mela Mulvihill, PhD, Scientist,
Biochemical & Cellular Pharmacology, Genentech
Difficult to drug targets require advanced biophysical methods for hit identification, characterization, and optimization through the early discovery hit-to-lead phase. Using case studies, I will present our advanced toolkit of novel mass spectrometry
and label-free biophysical assays used for screening, establishing mechanism of action, and kinetic measurements for compound optimization. The on-going projects I present will include a class of compounds that induce target degradation referred to
as Chemical Inducers of Degradation (CIDEs).
9:00 Networking Coffee Break
9:30 NMR Molecular Replacement: A Method to Probe Protein-Ligand Complexes in the Absence of Crystal Structures
Julien Orts, PhD, Professor, Laboratory
of Physical Chemistry, Swiss Federal Institute of Technology, ETH
I will describe our novel NMR2 (NMR Molecular Replacement) method which we believe provides an avenue for the fast and robust determination of atomic resolution binding pocket structure of ligand-protein complexes when obtaining well-diffracting crystals
is difficult. It is quicker than the current x-ray crystallography alternative of liquid-state NMR. I will present multiple NMR2 applications covering several ligand topologies ranging from peptidomimetic to small molecules that bind strongly or weakly
to protein receptors.
10:00 Moderated Discussion Session
Moderator: Ben Davis, PhD, Research Fellow, Biology, Vernalis Research
10:30 Studying Small Molecule-Membrane Protein Binding Kinetics Using Virion Oscillators
Guangzhong Ma, Graduate Student, Chemistry, Laboratory of N. Tao, Arizona State University
Our ‘membrane protein binding kinetics’ method measures binding induced charge change. We apply an alternating electric field to oscillate virions with GPCRs expressed on the surface and measure oscillation amplitude of the virions with sub-nm
precision. The binding of small molecule changes the charge on the virion surface and thus changes the oscillation amplitude. By tracking the oscillation amplitude in real-time, the binding kinetics can be obtained.
11:00 Enjoy Lunch on Your Own
1:00pm Chairperson’s Remarks
Mela Mulvihill, PhD, Scientist, Biochemical & Cellular Pharmacology, Genentech
1:05 CryoEM Applied to Drug Discovery
Seungil Han, PhD, Associate Research Fellow, Structure Biology & Biophysics, Pfizer Global R&D
1:35 Using Cryo-Electron Microscopy to Explore Endosomal GPCR Signaling
Alex Thomsen, PhD, Assistant
Professor, Department of Surgery, Columbia University
We are applying a variety of electron microscopy (EM) and computational methods to obtain high-resolution structural information about the megaplex of a single GPCR that interacts simultaneously with β-arrestin and G protein, and to visualize GPCR
signaling on the endosomal surface within living cells.
2:05 Structure-Based Drug Design with Cryo-EM Structures
Eric Therrien, Principal Scientist II, Schrödinger
The presentation will highlight our recent development to expand the applicability of structure-based drug design using Cryo-EM structures and their use to accelerate drug discovery at Schrödinger.
2:35 Networking Refreshment Break
3:05 The Critical Role of Biophysical Methods (with a Focus on SPR) in Advancing CDK7 Drug Discovery
Kristin
Hamman, MS, Research Investigator, Biochemistry, Syros Pharmaceuticals
We have established biochemical and biophysical methods to measure inhibition of CDK7 by both covalent and non-covalent inhibition. I will discuss our methods, focusing on our highly sensitive and robust SPR assay that has helped drive our lead
optimization efforts for a next-generation oral CDK7 inhibitor. These studies have allowed us to better understand how inhibitor potency and residence time affect CDK7 occupancy in cells and lead to anti-proliferation and apoptosis of CDK7 inhibitor-sensitive
cell lines.
3:35 Structural and Functional Characterization of Phospholipases as a Target for ALS
Jay Chodaparambil, PhD, Research Scientist, Chemical and Molecular Therapeutics, Biogen, Inc.
4:05 NMR and Enthalpy Screening of Combinatorial Libraries to Ligand Discovery
Maurizio Pellecchia, PhD, Professor of Biomedical sciences, UC Riverside, School of Medicine, Riverside, CA
We have recently proposed novel evolution-based ligand discovery approaches, in which the principles of positional scanning combinatorial chemistry and fragment-based drug design are combined with biophysical screening techniques, including NMR- and enthalpy-
based strategies, to identify novel ligands from large collections of compounds (105-106 or larger). I will reiterate the basic principles of the approaches and report several recent applications including tackling challenging drug targets.
4:35 Close of Conference
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