| High-Throughput
Parallel Chemistry Methods and Adoption |
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Introduction: High-throughput parallel synthesis is being widely implemented in many pharmaceutical companies and academic labs. Good implementation of high-Throughput Chemistry
(HTC) offers a lower-cost, faster way to develop more drug candidates. This session will outline some of the challenges to adoption of this technology and showcase some of its advantages and acceptance. |
8:20-8:30 Chairperson's Remarks
8:30-8:50 Parallel Synthesis of Novel Heterocyclic Libraries as Peptidomimetics
Dr. Robert Batey, Professor, Department of Chemistry, University of Toronto
Parallel synthetic strategies toward the development of novel heterocyclic compounds using both solution-phase and polymer supported strategies will be discussed. Synthetic methods that have been employed include the use of Cu catalysis,
electrocyclizations, and microwave-accelerated reactions. Of particular interest are the development of libraries based upon the conjugation of nitrogen heterocycles to peptides and
peptoids.
8:50-9:10 High-Throughput Parallel Synthesis Supporting Lead Generation in CropScience Research
Dr. Oliver Gurth, Bayer Crop Science
High-Throughput parallel synthesis is used as a valuable tool in the lead generation process in CropScience Research. Specific strength of the methodology is an eased establishment of
SAR, and quick response to biological and physicochemical results, making fast iterative optimization cycles possible.
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9:10-10:10 Panel: High-Throughput Parallel Synthesis: Methods and Adoption
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Dr. Christian
Paulitz, Team Leader, Lead Generation, Bayer CropScience AG
Dr. Ying Han, Senior Research Scientist, CombiChem, Albany Molecular Research, Inc.
Dr. Daryl R. Sauer, Group Leader, High-Throughput Organic Synthesis, Abbott Laboratories
Dr. Christopher Hulme, Head, High-Throughput Medicinal Chemistry, Lilly Corporate Center, Eli Lilly and Company
Dr. Robert Batey, Professor, Chemistry, University of Toronto
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10:10-11:10 Coffee Break, Exhibit and Poster Viewing
| Solubility
and Sample Stability In Solution |
| Introduction:
The solubility and stability of a compound in solution is critical to
getting reliable screening data. This session will highlight methods to
determine how soluble and how stable your sample is.
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11:10-12:10 Solubility in DMSO and in Water: The Hidden Killer in HTS
Dr. Christopher A. Lipinski, Adjunct Senior Research Fellow, Pfizer Inc.
Nobody running an HTS knows the true compound screening concentration. This results in missed actives, in "randomized" IC-50's, in wrong selectivity assessments and in irreproducible screening behavior. Understanding what goes wrong allows for correction of some but not all problems. Water uptake into DMSO coupled with freeze thaw cycles has a synergistic effect on causing compound precipitation from DMSO stock solutions. The bottom line for both chemistry and biology: DMSO used in compound storage and screening should be treated as if it were a water sensitive reagent.
12:10-12:30 Scale Matters: Building an Effective Computational Kinetic Solubility Model
Dr. Shaughn Robinson, Senior Scientist, Department Computational Chemistry, Pfizer Inc.
Presentation of the 3rd generation binary kinetic solubility model used at Pfizer. The model was built with a random forest algorithm using >40,000 data points. Prediction accuracy exceeds 85%. This talk will demonstrate the effectiveness of having large data sets available for training computational models.
12:30-12:50 Quality Enhancement of Large Chemically Diverse Compound Libraries - The Impact of Measuring Concentrations in Assay Buffer by
LC/CLND
Dr. Olga Issakova, Vice President, Analytical Chemistry, Nanosyn, Inc.
The development of a streamlined process for purifying and quantifying a large diverse library of compounds is presented. The issues of quality enhancement of compound collections will be discussed by an example of a 200,000 member compound library collected from several vendors. Special emphasis will be placed upon comparison of the concentrations measured in the assay plates diluted with buffer, and the concentrations of the compounds in stock DMSO solutions. The presented work is the result of joint collaborative efforts between Nanosyn and Amphora Discovery.
12:50-1:00 Sponsored Message (sponsorship available)
1:00-2:30 Lunch on your own
| Fragment-Based
Libraries and Screening Approaches |
| Introduction: This session will review the state-of-the-art in fragment-based screening and library design. It will include some recent examples of where fragment-based methods have helped identify and optimize leads. |
2:30-2:40 Chairperson's Remark
Dr. Ellen Laird, Principal Research Investigator, Computational Chemistry, Array BioPharma
2:40-3:00 Fragment-Based Screening and Ligand Design: Overview and Examples
Dr. Ellen Laird, Principal Research Investigator, Computational Chemistry, Array BioPharma
A review of the methodologies will be presented, including pros and cons of the various techniques. Several examples of note will be discussed. A computational approach practiced at Array will be described and exemplified.
3:00-3:30 Using NMR to Guide Fragment Based Drug Design
Dr. Jeffrey Huth, Senior Investigator, Structural Biology, Abbott Laboratories
Protein NMR methods for the discovery of low molecular weight leads, and examples of how these leads have been used to design pharmacologically active compounds will be presented. Some case studies highlight how fragment leads, coupled with structural information, can guide the design of focused libraries. Other studies demonstrate the effectiveness of core replacement strategies where a fragment lead was incorporated into a known high affinity compound to improve the physical properties. The strengths of using NMR to validate specific binding of low affinity leads, crucial to the success of the fragment based approach, will be emphasized.
3:30-4:30 Refreshment Break, Exhibit and Poster Viewing
4:30 -5:00 Tethering: Fragment-Based Drug Discovery
Dr. Daniel A. Erlanson, Senior Scientist, Sunesis Pharmaceuticals, Inc.
Building drugs from small molecular fragments offers key advantages over traditional methods: greater diversity can be more rapidly probed, and fragments are less likely to contain interfering functionalities. Fragment-based methods are particularly powerful when combined with structure-based drug design. At Sunesis we have developed Tethering®, which can experimentally identify small molecular fragments that bind site-specifically to a target of interest. A second-generation version of the technology, Tethering® with Extenders, facilitates not only the identification of fragments but also their assembly into inhibitors using dynamic combinatorial chemistry. We have used these methods to discover potent small molecule inhibitors against targets such as thymidylate
synthase, IL-2, and caspases.
| Flow Synthesis |
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Flow synthesis is emerging as an exciting new technology for miniaturized automated synthesis and purification of libraries. The following talks and poster illustrate the potential of this new field.
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Chairperson
Michael Hawes, Technology Application Leader, Syrris Ltd.
5:00-5:30 High-Throughput Drug Discovery
Dr. Brian Warrington, Vice President, Pharmaceutical Technology Development GlaxoSmithKline Pharmaceuticals
The pharma industry is in need of new paradigms for discovery and development of new drugs. Miniaturised methodology may hold the key to more effective and efficient processes.Some possible configurations will be explored.
5:30-6:00 The New Trickles, Flows and Floods in Organic Synthesis
Dr. Ian Baxendale, Director of new technology, Chemistry, University
of Cambridge
The talk will cover aspects of using flow reactor technology for multi-step
synthesis of key building blocks and natural products. This talk will be aimed at the synthetic chemist and will describe the latest synthetic approaches and developments in combining flow chemistry with solid-supported reagents.
Look for the following poster in this field!
Flow Reactors for Synthesis, Optimization and Library Generation
Michael Hawes, Technology Application Leader, Syrris Ltd.
Flow chemistry is an emerging technology with great potential for both discovery and process development. This poster describes a range of reactions performed and analyzed in a glass microreactor system, with automation of both synthesis and HPLC analysis. The paper also explains how the technology can be used in reaction optimization, library protocol generation, and creating purified libraries.
6:00-7:00 Networking Reception - Exhibit and Poster Viewing
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