NMR

Cambridge Healthtech Institute 第3届

Biophysical Approaches for Drug Discovery

( 药物开发的生物物理学途径 )

药物化学的新方法

2018年4月6日 | Hilton Bayfront | 加州圣地牙哥

 

近年来,可以侦测出物理性交互作用分子的生物物理学技术,以前所未有的规模导入了创药的现场。这是因为研究人员热衷于寻找不同于传统酵素抑制剂的新药物候选,代表需要侦测酵素/抑制剂活动的化学试验之外的手段。侦测蛋白质复合体抑制剂(蛋白质间交互作用抑制剂)及片段基础的先导化合物时,需要核磁共振(NMR)及表面等离子共振(SPR)等生物物理学试验。此外生物物理学方法的高通量也拓展了在化合物数据库筛选方面的应用,亦是这些技术受到高度注目的原因。在此可向药物开发生物物理学家、结构生物学家、计算机及药物化学家学习及交流,讨论研究的进展,听取个案研究的发表,学习生物物理学技术在寻找新先导化合物方面的最新应用方式。此外,各种方法的集成、对应计画需求所使用技术与时机的判断方法等相关讨论也是本届活动的注目焦点。


Final Agenda

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

* 活动内容有可能不事先告知作更动及调整。