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Fragment-Based Techniques

 


 Day 1 - Day 2 - Download Brochure 

 

Tuesday, April 7

12:30pm Registration

 

1:30 Chairperson’s Opening Remarks

Yoshitomo Hamuro, Ph.D., Director of Research, ExSAR Corporation

Mass Spectrometry

1:40 Fragment- Based Drug Design by Amide Hydrogen/Deuterium Exchange Mass Spectrometry

Yoshitomo Hamuro, Ph.D., Director of Research, ExSAR Corporation

The p38 mitogen-activated protein kinase (MAPK) pathway is an important intracellular signaling pathway involved in the production of proinflammatory and profibrotic mediators. Amide hydrogen/deuterium exchange (H/D-Ex) mass spectrometry (MS) is regularly used in the analysis of protein structure dynamics, protein–protein interactions, and protein–ligand interactions. Here, the binding sites of six different compounds targeting p38 MAPK were determined. Binding site locations were determined in the absence of ligand identity or chemical structure. A compound was identified that possessed the preferred binding specificities of two distinct compounds.

2:10 Native Mass Spectrometry:
An ESI Tool for Fragment Library Screening

Denis Zeyer, Ph.D., Chief Executive Officer, Alix

Non-covalent mass spectrometry is a biophysical method that allows detection and characterization of intact protein-compound complexes through accurate mass measurements. Combining high sensitivity and automation, this unique tool has emerged as an alternative screening method compare to NMR or SPR. We will present case studies involving mass spectrometry in the fragment-based drug discovery process.

Surface Plasmon Resonance

2:40 Use of SPR for Fragment Screening, HTS Hit Validation, and SAR Support in Drug Discovery

Tony M. Giannetti, Ph.D., Research Scientist, Biochemical Pharmacology, Genentech

Advances in surface plasmon resonance (SPR) biosensor technique have allowed applications of the technology to extend beyond protein-protein interactions to small molecule-protein interactions in the area of hit finding and hit validation. We have combined SPR with the techniques of traditional high throughput screening to develop a rapid procedure for hit identification from low molecular weight compound fragment libraries (MW < 300). Key features of the assay are the ability to screen and verify ~5000 compounds in a few weeks, large dynamic range of the assay (100 pM to 5 mM) and low amounts of protein used (< 0.5 mg from assay development through hit validation). Case examples of SPR-based hit identification, co-crystallization, and medicinal chemistry development of fragments will be presented.

3:10     Sponsored by:   FUJiFILM LifeSciences
Screening of a Metabolite-Based Fragment Library Using X-ray Crystallography and SPR

Alex Burgin, Chief Operating Officer, deCODE biostructures
We have developed a novel fragment library termed Fragments of Life (FOL) for structure-based drug discovery.  The FOL library includes natural small molecules of life, derivatives thereof, and bi-aryl protein architecture mimetics.  The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites and protein-protein interaction surfaces for fragment binding.  We screened FOL compounds against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography.  A portion of the FOL library was also screened by Surface Plasmon Resonance (SPR) using a Fujifilm AP-3000 SPR system.  There was overlap between fragments identified by X-ray and SPR screening methods, and several compounds identified by SPR could be observed in crystal structures.  A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H.  Analysis of the fragment-bound structures showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors. 

 

3:25 Networking Refreshment Break in the Exhibit Hall

4:05 Experimental Design in SPR Biosensor-based Fragment Screening

Peer Källblad, M.Sc. Ph.D., Chief Executive Officer, Beactica AB

SPR biosensor-based fragment screening will be exemplified with various drug targets including MMP 12, HIV-1 protease, HIV-1 reverse transcriptase & HCMV protease. The presentation focuses on different screening strategies, advantages, challenges and limitations of SPR biosensors. Furthermore, fragment library issues with special regard to the use of SPR biosensors will be discussed.

4:35 Use of SPR for Protein-Nucleic Acid Interactions

Farid Ahmed, Ph.D., Director, GEM Tox Consultants & Labs, Inc.

SPR has been used for a label free study of molecular interaction. Work carried out by myself and collaborators has shown that this powerful technique is capable of measuring the interaction and kinetic of DNA-protein binding in human cells irradiated with X-rays.

5:05 Breakout Discussions with the Experts

Topic 1: SPR – what we need to know
Moderator: Peer Källblad, M.Sc. Ph.D., Chief Executive Officer, Beactica AB

Topic 2: Selecting the right tools – what works?
Moderator: Denis Zeyer, Ph.D., Chief Executive Officer, Alix

Topic 3: How to choose the right fragments to move forward
Moderator: Tony M. Giannetti, Ph.D., Research Scientist, Biochemical Pharmacology, Genentech

6:15 End of Day

 


For more information on speaking opportunities:
Margit Eder, Ph.D., Conference Director
Cambridge Healthtech Institute
Phone: 781-972-5478
E-mail: meder@healthtech.com 

For Sponsor and Exhibit Information:
Suzanne Carroll, Business Development Manager
Cambridge Healthtech Institute
Phone: 781-972-5452
E-mail: scarroll@healthtech.com