Cambridge Healthtech Institute 제4회

Biophysical Approaches for Drug Discovery
(Drug Discovery를 위한 생물물리학적 접근)

의약화학 연구자를 위한 새로운 방법과 리드 화합물 생성 전략

2019년 4월 12일


최근 상호 작용하고 있는 생체분자를 계측하기 위한 생물물리학적 방법의 자동화가 진행되고 감도가 향상함으로써 Drug Discovery 분야의 진보가 가속하고 있습니다. 핵자기공명(NMR) 및 표면 플라즈몬 공명(SPR) 등을 이용한 바이오센서 기반 어세이, 등온적정형열량계(ITC), TSA(thermal shift assays)를 비롯한 각종 기술에 의해 단백질간 상호작용 및 복합막단백질을 표적으로 하는 화합물의 발견이 가능해졌습니다. 그러나 이 표적 클래스는 가용화가 어려우며, 기존 세포내 효소 표적과 달리 High Throughput Screening용 인비트로 기반 생화학적 기능 분석에 적합하지 않고 약제 개발이 어렵다는 문제가 있습니다. 따라서 리드 화합물을 생성하는 또 하나의 방법으로 기대되고 있는 것이 생물물리학적 기술에 크게 의존하는 프래그먼트 기반 약제 설계입니다. Drug Discovery를 위한 생물물리학적 접근을 테마로 한 이 심포지엄에서는 의약화학, 구조생물학, 생물물리화학, 컴퓨터 과학 등의 연구자가 한자리에 모여 생물물리학 분야의 최신 연구 성과 및 사례에 대해 검토하면서 리드 화합물의 효율적인 생성을 위해 이와 같은 성과를 적절한 타이밍에 활용하기 위한 전략에 대해 논의합니다.

Final Agenda

Friday, April 12

7:30 am Registration Open and Morning Coffee

생물물리학적 접근의 통합

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

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

생물물리학적 접근의 혁신

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 Engaging Kinases in Living Cells: Probing Drug-Target Interactions with Chemical Biology and Biophysical Tools

Jordan Carelli, PhD, Senior Scientist, Oncology RU, Pfizer

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 Sponsored Presentation (Opportunity Available)

11:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:00 pm Session Break


1:00 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 Sponsored Presentation (Opportunity Available)

2:35 Networking Refreshment Break

Drug Discovery에 대한 응용

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

Small molecule inhibition of CDK7 has been shown to have anti-proliferative effects on cancer cell lines and antitumor activity in mouse models. We have established methods to measure time-dependent inhibition of CDK7 by covalent compounds, which contributed to selection of a clinical candidate, SY-1365, currently in Phase I trials.

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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