Cambridge Healthtech Institute’s 3rd Annual

Biophysical Approaches for Drug Discovery

New Methods for Medicinal Chemists

April 6, 2018 | Hilton Bayfront | San Diego, California

Biophysical technologies, which detect molecules physically interacting with one another, are now employed in drug discovery more than ever. This is because researchers are more actively searching for new therapeutic candidates different from classical enzyme inhibitors, which requires moving beyond biochemical assays that detect enzyme/inhibitor activity. Detection of inhibitors of protein complexes (PPI inhibitors) or fragment-based drug leads needs biophysical assays such as those based on nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR). Further propelling biophysical techniques to the fore are advances in their throughput making them more amenable to compound library screening applications. Learn from and network with fellow drug discovery biophysicists, structural biologists and computational and medicinal chemists to discuss advances, hear examples of, and learn new applications of biophysical technologies in the endeavor of finding new drug leads. Other methods that may not be ‘pure biophysical’ but are new and not biochemical-based will also be a part of the program. Another focus of the meeting will be to highlight and discuss integration of various approaches and deciding ‘when to use what’ depending on a project’s needs.

Final Agenda

Friday, April 6

7:25 am Registration and Morning Coffee


7:55 Welcome and Opening Remarks

Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute

Pedro Serrano, PhD, Principal Scientist, Structural Biology and Biophysics, Takeda SD

8:00 FEATURED PRESENTATION: Development of Cryo-Electron Microscopy for Pharmaceutical Drug Design: From Implementation to Optimization

Christopher_ArthurChristopher Arthur, PhD, Principal Scientist Specialist, Structural Biology, Genentech

8:30 Application of Encoded Library Technology to Lead Generation at GSK

Svetlana_BelyanskayaSvetlana Belyanskaya, PhD, Encoded Library Technologies, R&D Platform Technology & Science, GSK Boston

Affinity-based screening of DNA-encoded chemical libraries is routinely employed within GSK for lead generation. The platform has evolved over its application to a quantitative on-DNA binding assay of billions of compounds simultaneously. A case study will be presented to illustrate the process of selection design and execution including the high throughput chemistry and hit confirmation using affinity selection mass spectrometry used to follow up screens.

9:00 Coffee Break

9:30 Native Mass Spectrometry and Collision-Induced Unfolding for Drug Discovery and Development

Varun V. Gadkari, PhD, Postdoctoral Research Fellow, Laboratory of Brandon Ruotolo, Department of Chemistry, University of Michigan

10:00 Identifying and Testing the Optimal Conditions for Kinetic Fragment-based Screening; a Novel TR-FRET Based Approach

David_SykesDavid Sykes, MS, Experimental Officer, Laboratory of Dmitry Veprintsev, Molecular and CelluPedro Serrano, PhD, Principal Scientist, Structural Biology and Biophysics, Takeda SDlar Pharmacology, University of Nottingham

Developing new approaches for studying drug-receptor kinetics is key to improving screening efficiency. I will describe a novel TR-FRET based competition-association kinetic binding approach testing the kinetics of a commercially available library of ~1400 low molecular weight fragments at the dopamine D2 receptor, a prototypical GPCR. A range of off-rates were obtained including examples with surprisingly slow off-rates. This approach offers the potential to discover chemical starting points for the development of kinetically optimized medicines.

10:30 Second-Harmonic Generation for Conformation-Selective Drug Discovery: PPI Case Studies

Joshua Salafsky, PhD, Founder & CSO, Biodesy, Inc.

I will review the state of the art in SHG technology with a number of case studies. In particular, I will discuss the sensitivity of SHG to subtle but biologically important allosteric conformational changes that occur in protein-protein interactions. Various approaches for setting up a protein-protein assay screen will be discussed as well.

11:00 Your Launchpad to New Fragment Space

Eric Jamois, PhD, Head of US Business Operations, Edelris

11:15 Enjoy Lunch on Your Own


1:00 Chairperson’s Remarks

Phillip Schwartz, PhD, Senior Scientist, Structural Biology and Biophysics, Takeda California

1:05 Takeda's Tool Kit of Biophysical Methods

Pedro Serrano, PhD, Principal Scientist, Structural Biology and Biophysics, Takeda SD

1:35 A Systematic Approach for Prosecuting Fragment Hits in the Absence of Structural Information

Bradley Doak, PhD, Research Fellow, Medicinal Chemistry, Monash University

Developing fragment hits into lead-like structures can be difficult, especially when no structural information is available. We aim to standardize the evaluation and development of these fragment hits, with or without structural information, through exploration of vectors around the fragment. Here we present case studies that used chemoinformatic tools for finding purchasable analogues as well as designing standardized libraries of reagents to explore and validate vectors for expansion.

2:05 Measuring Biomolecular Interactions of GPCRs Using a Variety of Biophysical Techniques

Phillip Schwartz, PhD, Senior Scientist, Structural Biology and Biophysics, Takeda California
Drug discovery efforts are undergoing a renaissance in GPCR-related research as orphan receptors become de-masked and our understanding of how to study these difficult targets improves. Identifying preparations amenable to biophysical characterization is a critical step in pursuing GPCR drug development. I will discuss the application of three biophysical techniques (surface palsmon resonance, second harmonic generation and nuclear magnetic resonance) to GPCRs.

2:35 Networking and Discussion Session
Moderator: Roderick E. Hubbard, PhD, Professor, University of York and Director, Vernalis

3:05 Refreshment Break


3:35 Coupling Biophysical Approaches with Molecular Simulations to Optimize Compounds for Challenging Disease Targets

Woody_ShermanWoody Sherman, PhD, CSO, Silicon Therapeutics

We describe our drug discovery projects that combine experimental and simulation methods to develop novel medicines for diseases with targets that are currently considered challenging. Our INSITE computational platform accurately treats the underlying physics of molecular recognition (i.e. protein dynamics, water thermodynamics, and quantum mechanical effects) and integrates with experimental techniques such as X-ray crystallography, NMR, ITC, and second harmonic generation.

4:05 Liquid Chromatography- Mass Spectrometry (LC-MS)-Based Metabolomics in Pharmacological Lead Generation: From a Single Metabolic Node to Network Analysis

Gang_XingGang Xing, PhD, Principal Scientist, Internal Medicine Research Unit, Pfizer Worldwide Research & Development, Pfizer, Inc.

The study of metabolic disease is complicated by sophisticated pathway networks contributing both catabolically and anabolically to a single molecular entity. LC-MS offers the ability to detect and quantify biomarkers with both specificity at single nodes and comprehensive coverage of large, chemically diverse networks, empowering not only SAR-based lead compound generation but also unknown pathway explorations. Case studies on both topics will be presented.

4:35 End of Conference