NMR

Cambridge Healthtech Institute 第3回

Biophysical Approaches for Drug Discovery

( 創薬に対する生物物理学的アプローチ )

医薬品化学の新たな手法

2018年4月6日 | Hilton Bayfront | カリフォルニア州サンディエゴ

 

近年、物理的な相互作用のある分子を検出することができる生物物理学的な技術が、かつてない規模で創薬の現場に導入されるようになっています。この背景には、従来の酵素阻害剤と異なる新たな治療薬の候補を積極的に探し求める動きが研究者の間で広がっており、これらの酵素や阻害剤の活性を検出する生化学分析以外の手段が必要になっているという事情があります。タンパク質複合体阻害剤 (タンパク質間相互作用阻害剤) やフラグメントベースのリード化合物を検出するには、核磁気共鳴法 (NMR) や表面プラズモン共鳴法 (SPR) をベースにした生物物理学的アッセイが必要になります。また、生物物理学的な手法のスループットが高まり、化合物ライブラリーのスクリーニングに利用できる余地が広がったことも、この技術の注目度を高める要因となっています。このカンファレンスプログラムでは、創薬に携わっている生物物理学、構造生物学、計算化学、医薬品化学などの研究者と意見を交換し、交流を深めながら、研究の進捗状況について議論し、ケーススタディの発表を聞き、新たなリード化合物の発見に向けた取り組みのなかでの生物物理学的技術の新たな用途について学ぶことができます。また、各種アプローチの統合やプロジェクトのニーズに応じて使用する技術とタイミングを判断する方法などに関する議論も今回のプログラムの焦点となります。


Final Agenda

4月6日 (金)

7:25 am Registration and Morning Coffee

創薬のための新たな手段−生物物理学的な手段とその他の手段

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

生物物理学の直交的なアプローチ

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

生物物理学的なアプローチによる困難な標的への対応

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

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。