Cambridge Healthtech Institute 第3届
Biophysical Approaches for Drug Discovery
( 药物开发的生物物理学途径 )
2018年4月6日 | Hilton Bayfront | 加州圣地牙哥
Friday, April 6
7:25 am Registration and Morning Coffee
EMERGING TOOLS FOR DRUG DISCOVERY - BIOPHYSICAL AND BEYOND
7:55 Welcome and Opening Remarks
Anjani Shah, PhD, Conference Director, Cambridge Healthtech Institute
Chris Smith, PhD, Director, Medicinal Chemistry, COI Pharmaceuticals
8:00 FEATURED PRESENTATION: Development of Cryo-Electron Microscopy for Pharmaceutical Drug Design: From Implementation to Optimization
Christopher Arthur, PhD, Principal Scientist Specialist, Structural Biology, Genentech
8:30 Application of Encoded Library Technology to Lead Generation at GSK
Svetlana 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
Brandon T. Ruotolo, PhD, Associate Professor, Department of Chemistry, University of Michigan
10:00 Solid-State NMR for Peptide Drug Optimization
Yongchao Su, PhD, Associate Principal Scientist, Head, Pharmaceutical NMR Lab in Preclinical Sciences, Merck & Co., Inc.
We used solid state (ss) NMR to determine the high-resolution structure of fibrils from a pharmaceutical peptide. This is the first time in pharmaceutical sciences that a high resolution molecular structure of insoluble aggregate of a peptide drug has been determined. The structure enabled us to identify and test residues in the fibril core that lead to backbone rearrangement, which should facilitate optimization of peptide drugs with lower risks of aggregation.
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 Measure What Matters, When It Matters
Delphine Collin, PhD, Vice President, Discovery and Biophysics, HarkerBIO, LLC
By changing their conformation, proteins can carry out their functions and modulate the functions of other molecules. As structure based drug discovery's appreciation of proteins as dynamic, flexible molecules grows, so does the importance of probing conformational changes to the unliganded form of a protein. Triaging our toolbox of orthogonal techniques, including second harmonic generation measurements, we can investigate and measure protein structural motion.
11:15 Luncheon Presentation (Opportunity Available) or Enjoy Lunch on Your Own
12:00 pm Session Break
ORTHOGONAL BIOPHYSICAL APPROACHES
1:00 Chairperson's Remarks
Phillip Schwartz, PhD, Senior Scientist, Structural Biology and Biophysics, Takeda California
1:05 Novel Approaches in Using NMR and SPR for Fragment Hit Identification and Validation
Anil Padyana, PhD, Associate Director, Structural Biology and Biophysics, Department of Biochemistry, Agios Pharmaceuticals
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 Takeda's Tool Kit of Biophysical Methods
Pedro Serrano, PhD, Principal Scientist, Structural Biology and Biophysics, Takeda SD
2:35 Networking and Discussion Session
3:05 Refreshment Break
ADDRESSING CHALLENGING TARGETS WITH BIOPHYSICAL APPROACHES
3:35 Coupling Biophysical Approaches with Molecular Simulations to Optimize Compounds for Challenging Disease Targets
Woody 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 Characterization of Wild Type GPCRs Using Surface Plasmon Resonance
Iva Navratilova, PhD, Staff Scientist, Department of Molecular Biology, University of Dundee
Expressing, purifying and analysing membrane proteins using SPR is routinely challenging. In this presentation, we will present our latest results demonstrating a scalable method for the successful development of SPR assays for a wide range of wild-type GPCRs. The SPR assays can be exploited for fragment screening and kinetic characterization to discover novel ligands.
4:35 Liquid Chromatography- Mass Spectrometry (LC-MS)-Based Metabolomics in Pharmacological Lead Generation: From a Single Metabolic Node to Network Analysis
Gang 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.
5:05 End of Conference