2013 Archived Content
Fragment-Based Drug Discovery
From Discovery to Lessons Learned
April 16-17, 2013
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WEDNESDAY, APRIL 17
7:45 am Continental Breakfast Breakout Discussions
In this interactive session, several topics will be offered for discussions and delegates are invited to join the moderated discussion at hand. In this informal setting, participants are encouraged to share examples from their work, vet ideas with peers and be part of a group problem-solving endeavor.
Topic: Fragment-finding smackdown
Moderator: Daniel Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.
Are some fragment-finding methods more (or less) reliable than others?
At what point do you consider a fragment hit validated?
What do you do with fragments that don't confirm in orthogonal assays?
Topic: Bottlenecks for Fragments
Moderator: Roderick E. Hubbard, Ph.D., Senior Fellow, Vernalis (R&D) Ltd.; Professor, University of York, UK
Integrating fragments into an organisation
Fragments for non-conventional targets
Screening methods - myths and reality
Topic: Everything Dan and Rod are NOT Discussing
Moderator: Edward R. Zartler, Ph.D., President & CSO, Quantum Testing Consulting
Topic: Strengths And Limitations Of The Fragment Approach
Moderator: Kevin Burgess, Ph.D., Professor, Department of Chemistry, Texas A&M University
• Examples of outstanding successes and failures
• Can we identify the Achilles Heel of the method that prevents it being more widely applied
• What is on the horizon for tackling that issue
8:55 Chairperson’s Opening Remarks
Daniel Erlanson, Ph.D., Co-Founder, Carmot Therapeutics, Inc.
9:00 Beyond Consensus: Leveraging Biases Inherent in Different Fragment Based Screening Technologies
Peter S. Kutchukian, Ph.D., Presidential Postdoctoral Fellow, Novartis Institutes for BioMedical Research, Cambridge, MA
A first step in FBDD often entails a fragment-based screen (FBS) to identify fragment “hits.” While there are theoretical advantages of using FBDD at the earliest stages of a drug discovery program, hurdles such as the integration of conflicting results from orthogonal screens have hindered its success. We present the meta-analysis of 34 fragment based campaigns at Novartis, which used a generic 1,400 fragment library against diverse targets families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we aim to answer three questions: 1) What makes a fragment amenable for FBS? 2) How do different FBS technologies compare with each other? 3) What is the best way to pair FBS assays? In addition to identifying properties that render fragments amenable for FBS, we compare in an unprecedented scale various screening technologies. Through our analysis we elucidate specific technology biases in detecting or missing fragment hits at a substructural level. Furthermore, we have developed a method to efficiently combine technologies based on these biases, in order to minimize the overall bias inherent in any screening campaign.
9:30 Enabling Chemical Discovery through the Lens of a Computational Microscope
Rommie E. Amaro, Ph.D., Assistant Professor, Department of Chemistry, University of California, San Diego
With exascale computing power on the horizon, computational studies have the opportunity to make unprecedented contributions to drug discovery efforts. Steady increases in computational power, coupled with improvements in the underlying algorithms and available structural experimental data, are enabling new paradigms for discovery, wherein computationally predicted ensembles from large-scale biophysical simulations are being used in rational drug design efforts. Such investigations are driving discovery efforts in collaboration with leading experimentalists. I will describe our work in this area that has provided key insights into the systematic incorporation of structural information resulting from state-of-the-art biophysical simulations into protocols for inhibitor and drug discovery, with emphasis on the discovery of novel druggable pockets that may not be apparent in crystal structures.
10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Fragment-Based Discovery of Novel, Selective PI3Kβ Inhibitors as Anti-Thrombotic Agents
Fabrizio Giordanetto, Ph.D., Project Leader, Principal Scientist, Medicinal Chemistry, CVGI iMed, AstraZeneca R&D
Structure-based evolution of the original fragment hits coupled with property-based design resulted in the identification of potent, selective Phosphoinositide 3-kinases (PI3K) p110β isoform inhibitors with favourable in vivo antiplatelet effect. Despite the antiplatelet action, no significantly increase in bleeding time was observed. Additionally, due to the engineered selectivity over p110α, no insulin resistance was induced.
11:15 The de novo Fragment-Based Drug Discovery of ITK Inhibitors
Heather Twin, Ph.D., Research Scientist, Vertex Pharmaceuticals
Interleukin-2 inducible T-cell kinase (Itk) is a member of the Tec family of non-receptor protein kinases which plays a central role in T-cell signalling. Inhibition of Itk presents an attractive approach for the treatment of autoimmune and allergic diseases. X-ray crystallography was used to aid the design of a series of potent and selective Itk inhibitors.
11:45 End of Conference
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