Day One: Monday, February 23

7:30-8:30 Coffee and Registration

8:30-8:40 Chairperson’s Remarks
Assistant Professor R. Kip Guy, Pharmaceutical Chemistry, Director, Bay Area Screening Center; Director, Center for Chemical Diversity, UCSF

8:40-9:25 Keynote Address: Chemical and Biological Approaches for the Preparation of Libraries Professor Kim D. Janda, Department of Chemistry, Ely R. Callaway, Jr., Chair in Chemistry, The Scripps Research Institute Past and recent investigations of our work based on the preparation and screening of chemical and biological libraries will be presented. When appropriate, an emphasis will be placed on screening of these libraries for the identification of biological activity.

Diversity-Oriented Synthesis versus Target-Oriented Synthesis

9:25-9:55 RADDAR-a New Paradigm for Hit & Lead Creation
Dr. Konrad Bleicher, Head of Combinatorial Chemistry, F. Hoffmann-La Roche Ltd, Pharmaceuticals Division Lead Generation
Roche Adaptive Drug Design And Refinement is the consequent integration of library design, combinatorial chemistry and compound testing (multidimensional optimization) for the generation of targeted, high-quality, compound libraries. The successful application of this approach will be discussed using both solution and solid phase chemistry technologies. The impact of RADDAR within a chemogenomics platform will also be addressed.

9:55-10:25 Diversity-Oriented Libraries Tailored for Forward Chemical Genetics
Dr. John A. Tallarico, Head of Chemical Technology, Harvard Institute of Chemistry and Cell Biology, Harvard Medical School
Ongoing research towards the development and realization of skeletally diverse, split-pool libraries will be presented. Our strategies will be discussed in detail and several screening results will be included from in vitro and whole cellular assays.

10:25-10:55 Networking Coffee Break

10:55-11:25 Affinity Screening and Mixture-Based Libraries
Dr. Steven P. Adams, Chief Scientific Officer, Neogenesis Pharmaceuticals, Inc.

11:25-11:55 Is Maximizing Diversity in Library Synthesis Useful?
Dr. Anil Nair, Senior Scientist, Aventis Combinatorial Technology Center
Design of chemical libraries involves several aspects such as lead-like properties, target/target-family relevant chemical space, synthetic feasibility, etc. Maximizing diversity around a chemical scaffold (chemotype) has to be balanced against above parameters, particularly conformational flexibility of compounds. In addition, limitations of high throughput screening capabilities and cost of synthesis also play important roles while designing libraries. The diversity aspect in library design will be discussed with case studies involving kinase and GPCR targets with focused and generic libraries.

11:55-12:25 DOS versus TOS Panel Discussion

12:25-2:00 Lunch on your own
(technology workshop, sponsorship available)

Library Design
Addressing the Trend Toward Smaller,
More Focussed Libraries for Drug Discovery

2:00-2:10 Chairperson's remarks
Dr. Aubrey Mendonca, VP Business Development, Polymer Laboratories

2:10-2:40 Discovery of Ligands for Melanocortin Receptors
Dr. Matthew Fisher, Head, Discovery Chemistry Research - Lead Generation Lilly Research Laboratories
A survey of ligands for a variety of G-Coupled Protein Receptors (GPCR's) reveals striking structural similarities. Use of these common structural motifs (privileged structures) as key diversity elements in new compound libraries has proven to be an effective strategy for the identification of novel ligands for GPCR's. The melanocortin receptors belong to the Class A family of GPCR's and have generated sufficient interest for a variety of clinically relevant indications. Our presentation will describe our approach to the identification of lead structures for these receptors and to highlight the use of privileged structures in GPCR ligand design.

2:40-3:10 Design and Synthesis of a Lead Generation Library Targeting Protein-Protein Interactions
Dr. Jürgen Hinrichs, Laboratory Head, Combinatorial Chemistry Unit, Novartis Institutes for Biomedical Research
Natural and synthetic structures based on a cyclic peptide chain connected to a biaryl moiety have been shown to possess potent biological activities. To overcome the limitations of alpha-peptidic structures, like low bioavailability and easy proteolysis, we have designed peptido-mimetic macrocycles containing beta-amino acids. Whereas the tripeptide can mimic a beta-turn, the biaryl part (with the appropriate substitution pattern) should be capable of acting like an alpha-helix. We will report the development of a solid-phase protocol for the synthesis of biaryl-containing macrocyclic beta-peptides, aiming to interrupt protein-protein interactions.

3:10-3:40 Knowledge Integrated Multiparametric Library Design
Dr. M. Patek, Senior Research Scientist, Selectide-Aventis Combinatorial and Technology Center, Aventis Pharmaceuticals
In the process of a library design, one frequently faces a competing nature of important library criteria. New approaches to the combinatorial library design are thus highly desirable. As a part of the integrated library design program, we were focusing on the major challenge, specifically, how to efficiently and most objectively optimize the library size and format simultaneously with other important properties such as diversity, compound properties, reagent reactivity, and cost. The adaptation of a multi-objective genetic algorithm (MOGA) and multiple weighted inputs to the library design is presented, that results in a family of solutions and provides users with informed choices at any stage of the drug discovery process.

3:40-4:10 Networking Refreshment Break

4:10-4:40 Nonleadlikeness and Leadlikeness in Biochemical Screening
Dr. Gilbert M. Rishton, Research Scientist, Amgen
Biochemical assays have largely supplanted functional biological assays as drug screening tools in the early stages of drug discovery. The de-selection of compounds that are "nonleadlike" binders (and bonders) and the proactive selection of those compounds that are "leadlike" in their binding to the target are vital components of the screening effort. The physiochemical properties of leadlikeness and the surprising differences between those properties and the now classical definitions of druglikeness are becoming apparent.

4:40-5:10  A Computer Based Strategy for Synthesizing Structurally Diverse Compound Sets
Dr. William F. Michne, Senior Principal Scientist, AstraZeneca
High throughput screening of corporate compound collections is pro-ducing large numbers of hits for which bulk solid sample is not available for further study. Taken individually the compounds are for the most part readily resynthesized. However, given the large and growing numbers of such compounds, coupled with their overall structural diversity, the resyn thesis of these compounds is generally considered impractical. As result, the compounds are ignored, quite possibly leaving many valuable drugs undiscovered in the longer term. We are exploring methods for developing "synthesis matrices" for structurally diverse compound sets that allow many reactions to be compressed into a smaller number of syn-thetic operations, thereby making the preparation of a large percentage these compounds a realistic exercise.

5:10-540 Panel Discussion

5:40-6:30 Reception, Exhibit and Poster Viewing
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6:40 Close of Day