Exploiting Molecular Diversity

In the early 1990s it was believed that combinatorial chemistry would revolutionize the drug discovery industry. Ten years later the route from design and synthesis of compound libraries to identification of lead structures is still long and costly. Synthesis of an almost unlimited number of organic compounds covering as much of chemistry space as possible is no longer the most cost-effective and time-saving approach to hit identification. Creating libraries by using biological target structure to inform chemical design, facilitated by quantum advances in structural genomics and computational capabilities, is a smarter, more efficient way to produce good initial leads. Considering solubility, permeability, and other druglike properties early in library design and introducing both target and lead structural constraints in lead development are further ways to ensure that more compounds make it to trial. Anyone interested in learning how to develop more effective libraries faster and cheaper, as well as learning from case studies where informed design in conjunction with novel assay development has been successful, should attend this meeting.

SCIENTIFIC ADVISORS/SESSION CHAIRS
Dr. Kevin Burgess, Texas A&M University
Dr. Alexander Doemling, Morphochem AG
Dr. Adam Golebiowski, Procter & Gamble Pharmaceuticals
Dr. Benjamin E. Rich, Brigham and Women's Hospital
Dr. Alexander Tropsha, University of North Carolina at Chapel Hill

ADDITIONAL SPEAKERS
Dr. Manfred Auer, Novartis
Dr. Nigel R.A. Beeley, Arena Pharmaceuticals, Inc.
Dr. Paul Beroza, Telik, Inc.
Dr. Irwin Chaiken, University of Pennsylvania School of Medicine
Dr. Walter Cristofoli, Advanced ChemTech
Dr. Li Di, Wyeth-Ayerst Research
Dr. Alexey V. Eliseev, State University of New York at Buffalo and Therascope AG
Dr. Peter Grootenhuis, DuPont Pharmaceuticals Research Laboratories
Dr. Klaus Gubernator, Senomyx, Inc.
Dr. Mark Hermsmeier, Bristol-Myers Squibb
Dr. Eric A. Jamois, Accelrys Inc.
Dr. Daria Jouravleva, Advanced Chemistry Development, Inc.
Dr. Christopher A. Lipinski, Pfizer Global Research and Development
Dr. Gary W. Luehr, Versicor, Inc.
Dr. Jacques Mauger, Selectide, Aventis Pharma
Dr. Daria Jouravleva, Advanced Chemistry Development, Inc.
Dr. Günther Metz, Graffinity GmbH
Dr. Tudor I. Oprea, AstraZeneca R&D
Dr. Kirk Simmons, DuPont Crop Protection
Dr. David Spellmeyer, Signature BioScience, Inc.
Dr. S. Stanley Young, GlaxoSmithKline

DRUGLIKE CHARACTERISTICS AND BIOLOGICAL RELEVANCE
Constructing Combinatorial Library Filters: "Rule of 5" and More
Increasing Pharmacokinetics Awareness in Early Drug Discovery
High-Throughput Physicochemical Profiling for Optimization of Druglike Properties
Chemical versus Pharmacological Diversity
Informative Design and Model Building in Drug Discovery

LIBRARY SCREENING FOR SMALL MOLECULE LEADS
Dynamic Combinatorial Chemistry
Confocal Nanoscanning-Bead Picking-AIDA Technology (CONA-HTS)
Sequential Screening: Cut Compounds Screened by 80% and Find All the Hits You Need
Small Molecules for Large Interactions
Systematic Diversity Scan and Selective Lead Evolution on Chemical Microarrays

RESULTS FROM TARGET-FOCUSED LIBRARIES
An Update on Drug Discovery at GPCRs
Identification of Better JAK Kinase Inhibitors with Cell-Based Assays
Combinatorial Chemistry in Chemosensory Molecular Discovery
Exploring Receptor Recognition and Recognition Mimetics Using Epitope Randomization
Combinatorial Lead Discovery of Antimicrobial Oxazolidinones
From Target Family Directed Library To Target Specific Dedicated Library: A Winning Approach In Drug Discovery

COMPUTATIONALLY DRIVEN LIBRARY DESIGN TO LEAD DISCOVERY
Combinatorial Chemistry Informatics and Library Design for Integrated Lead Discovery in Pharmaceutical Research
Predictive QSAR Modeling: Applications to Data Mining
Practical Outcomes of Data Mining in-Vivo HTS Data
WaveScreen: A Novel Approach For Drug Discovery
Accurate Prediction of Aqueous Solubility
Computationally Driven, High-Throughput Lead Discovery Using Predictive Substructural Analysis
Design of Drug-Like Combinatorial Libraries - An Application of Constrained Diversity

7:30am Registration, Poster and Exhibit Viewing, and Light Continental Breakfast

8:30 Chairperson's Opening Comments
Dr. Christopher A. Lipinski, Senior Research Fellow, Pfizer Global Research and Development

8:40 Keynote Presentation:
Constructing Combinatorial Library Filters: "Rule of 5" and More
Dr. Christopher A. Lipinski
Constructing combinatorial library filters depends both on an understanding of how chemistry space differs between phase II drugs and combinatorial libraries and on an appreciation of the trade-offs inherent between chemical synthesis feasibility and the synthesis of compounds with druglike properties. Combinatorial library filters should focus most heavily on those parameters that are least under medicinal chemistry control.

9:20 Increasing Pharmacokinetics Awareness in Early Drug Discovery
Dr. Tudor I. Oprea, Associate Director, EST Lead Informatics and Medicinal Chemistry, AstraZeneca R&D
The Lipinski "Rule of 5" was derived for drugs, not leads. An analysis of over 100 lead:drug pairs indicates that lower molecular weight and lower lipophilicity are advisable in leadlike library design. VolSurf, designed for modeling pharmacokinetic properties (e.g., passive permeability and solubility), is effective in estimating binding affinity (i.e., as a receptor-based scoring function). In combination with ChemGPS, our own method to estimate molecular similarity, VolSurf can be used to rapidly rule out compounds outside the targeted range for permeability and solubility. Traditionally, binding affinity is usually screened for, and optimized, first-while pharmacokinetic properties are left for a later stage. The paradigm shift we are witnessing is simultaneous optimization of both affinity and pharmacokinetic properties in the early stages of drug discovery.

9:50 High-Throughput Physicochemical Profiling for Optimization of Druglike Properties
Dr. Li Di, Senior Scientist, Chemical Sciences Department, Wyeth-Ayerst Research
High-throughput solubility, permeability, and pKa assays for profiling discovery compounds will be discussed. Multivariate data analysis is applied to derive predictive models for drug and property design. The activity and property information can be incorporated into designing combinatorial libraries that are more potent and more druglike.

11:00 Chemical versus Pharmacological Diversity
Dr. Paul Beroza, Assistant Director, Chemoinformatics, Telik, Inc.
Computational approaches to molecular diversity have focused primarily on chemical descriptors of molecules. The in silico representation of atoms and bonds is translated into a more abstract representation that can be used to assess similarity and dissimilarity among a set of molecules. Concepts relating to druglike characteristics of molecules and the use of more biologically relevant descriptors are becoming increasingly important. TRAP (Target Related Affinity Profiling) represents an operational approach to molecular diversity in which a compound is described by a unique affinity fingerprint that is determined by the compound's ability to bind to a select panel of proteins. Molecules can be classified according to their affinity fingerprints enabling rapid and efficient identification of therapeutic leads. The merits of this approach will be compared with more traditional chemical approaches to molecular diversity and considered in the context of lead identification for novel therapeutic targets.

11:30 Informative Design and Model Building in Drug Discovery
Dr. Peter Grootenhuis, Senior Director, Computational Sciences, DuPont Pharmaceuticals Research Laboratories
Informative design is a novel experimental design strategy that leads to computational models that are very effective in assisting medicinal chemists in various stages of the drug discovery process. It is based on concepts from information theory and works best when carried out in iterative, design-parallel, synthesis-screening cycles. Successful applications of informative design include the rapid identification of structurally diverse leads by library design, construction of computational models for P-glycoprotein selectivity, and the generation of informative gene family screening libraries.

12:00 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

2:00 Chairperson's Comments
Dr. Alexander Doemling, Vice President, Chemistry, Morphochem AG

2:05 Dynamic Combinatorial Chemistry
Dr. Alexey V. Eliseev, State University of New York at Buffalo; and Director of Chemistry, Therascope AG
This lecture will present dynamic combinatorial chemistry (DCC), an approach to molecular diversity generation and screening that involves reorganization of pools of compounds existing in a dynamic equilibrium via their interactions with the target. Such reorganization results in the formation of amplified amounts of those components that form the strongest complexes with the target and thereby simplifies their isolation and identification. DCC offers a new approach to drug discovery that combines library synthesis and screening in a single step and allows the rapid exploration and customization of pharmaceutical diversity space for a given target. We will consider most recent examples of the use of DCC to discover novel ligands for proteins and nucleic acids.

2:35 Confocal Nanoscanning-Bead Picking-AIDA Technology (CONA-HTS): A Methodology for Drug Discovery with Orphan Molecular Targets and Combinatorial Chemistry on the Solid Surface
Dr. Manfred Auer, Novartis Leading Scientist, Innovative Screening Technologies, Novartis
To optimally exploit combinatorial solid-phase organic chemistry and new orphan targets from functional genomics and proteomics, Novartis and EvotecOAI developed the CONA-HTS (confocal nanoscanning-bead scanning picking-AIDA technology) as a novel high-throughput, low-hit-rate, miniaturized HTS screening process. The hit identification process is based on a series of quantitative selection criteria for the consecutive exclusion of false positives and artifacts on the solid surface and in solution. The process combines a new instrument called PickoScreen with a proprietary blue fluorescent dye (AIDA) technology in combinatorial split-and-mix synthesis.

3:05 Sequential Screening: Cut Compounds Screened by 80% and Find All the Hits You Need
Dr. S. Stanley Young, Head, Research Statistics Unit, GlaxoSmithKline
Statistical selection of initial screening sets can produce a small but real increase in initial hit rates. Statistical analysis of initial screening results can give SAR models that can increase hit rates ten- to fortyfold. These methods can be used in a sequential paradigm to reduce the number of compounds screened by 80 to 90%. Sufficient hits are found to feed into lead development programs while costs are dramatically reduced.

4:15 Small Molecules for Large Interactions
Dr. Alexander Doemling
Protein-protein interactions (PPI) as drug targets are an emerging theme in the medicinal chemistry community. Nevertheless, many typical products of the biotech industry (e.g., epo, insulin, hGH) are still waiting for their small molecule successor. We will show how the power of new multicomponent reaction chemistry (MCR), together with a new way to screen PPI, can be leveraged to find small molecules that are either antagonists or agonists of hormones or cytokines.

4:45 Systematic Diversity Scan and Selective Lead Evolution on Chemical Microarrays
Dr. Günther Metz, Head of Computational Discovery Technologies, Graffinity GmbH
Graffinity has developed a novel small molecule screening platform combining chemical microarrays, label-free affinity detection, and a fully integrated process for small molecule optimization. The technology is applied to the screening of leadlike, fragment-based compound collections against protein targets providing direct access to comprehensive structure-affinity maps. The ability to start from weak but specific binding provides an early entry point for SAR analysis and circumvents problems associated with traditional approaches using libraries of substantial size and compound complexity. Mapping and understanding molecular interactions related to small structural variations are facilitated by a new, proprietary, chemistry-oriented data visualization and analysis tool. We will present this novel approach, demonstrate the microarray data analysis, and show how information-driven screening results in potent leads with a systematic optimization history.

5:15 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

8:30 Chairperson's Comments
Dr. Benjamin E. Rich, Department of Dermatology, Brigham and Women's Hospital

8:35 An Update on Drug Discovery at GPCRs
Dr. Nigel R.A. Beeley, Vice President and Chief Chemical Officer, Arena Pharamceuticals, Inc.
We have previously reported on proof of principle for CART™ (Constitutively Activated Receptor Technology), particularly useful for identifying novel molecules that interact with G-protein coupled receptors (GPCRs). We have now assembled additional tools, including Melanophore technology and Affymetrix Genechip™ technology, to execute Project Genesis, a massively parallel, multifaceted program with the objective of completing drug discovery at all therapeutically relevant GPCRs within the next five years. New results include the identification of inverse agonists, agonists, and allosteric modulators at selected receptors, some of which show potential in vivo in appropriate models.

9:05 Identification of Better JAK Kinase Inhibitors with Cell-Based Assays
Dr. Benjamin E. Rich
The Janus (JAK) family of nonreceptor tyrosine kinases are essential for cellular responses to several cytokines and are therefore attractive targets for pharmaceutical intervention. Tyrphostins are a class of compounds that inhibit a number of protein tyrosine kinases including the JAK kinases. Although the most potent of these, AG490 or B42, has an IC50 of 10 to 20 micromolar, it can block the responses of various cells to a number of cytokines by inhibiting both JAK2 and JAK3 kinases. Cellular responses to IL-3, -5, -6, -12, IFN-gamma, and GM-CSF depend upon JAK2 while responses to IL-2, -4, -7, -9, and -15 require JAK3. By inhibiting both of these kinases, AG490 exerts broad suppressive effects on the immune system. In an effort to identify compounds that are more selective and potent inhibitors of the JAK kinases, simple cell proliferation assays relying on JAK2 and JAK3 were used to screen a library of 600 derivatives of AG490. Two related derivatives were found to be significantly better inhibitors. These molecules have IC50 values of 2 to 5 micromolar. Ongoing efforts are focused on further screening as well as in vitro and in vivo evaluation of the new compounds.

9:35 Combinatorial Chemistry in Chemosensory Molecular Discovery
Dr. Klaus Gubernator, Vice President, Chemistry, Senomyx, Inc.
The recently identified olfactory and taste receptors offer intriguing discovery opportunities for novel ways to modulate smell and taste. Emerging technologies of rapid target identification, validation, screening, and lead optimization could be applied to these receptors with unique efficiency. Chemosensation offers an unparalleled potential of rapid functional testing and feedback to discovery. Tight integration of a complete suite of discovery disciplines is crucial for efficiency in molecular discovery. Recent advances in the functional characterization of taste and olfactory receptors and their role in sensory perception will be presented, and an outlook on the potential impact of these discoveries on chemosensory research using combinatorial chemistry and high-throughput organic synthesis will be given.

10:45 Revealing and Utilizing Receptor Recognition Mechanisms in a High Throughput World
Dr. Irwin Chaiken, Research Professor of Medicine and Director of Protein Interactions Core, University of Pennsylvania School of Medicine
Recent genomic mapping promises to identify essentially all of the proteins that underpin normal and aberrant biology in humans. What genomics leaves undone is to determine how these proteins interact and integrate into molecular pathways in health and disease. Specific molecular interactions provide the fundamental mechanism for selectivity in virtually every aspect of biological structure and function. The convergence of structural and mutational studies makes it possible to define what parts of a protein are important for recognition. Still, knowing what is important does not necessarily foretell how binding epitopes actually function. We have applied the approach of epitope randomization on phage to explore how structural elements in such receptor recruitment systems as interleukin 5 and HIV-1 function in receptor recognition. This work has led in the IL5 case to differentiation of recognition and activation epitopes, and this in turn has potential to help in the design of non-activating mimetics that could stimulate development of therapeutic antagonists for allergic inflammations such as asthma. Whether it is possible to differentiate recognition and activation in designing inhibitors in cases such as HIV-1 cell attachment and infection remains a tantalizing but unsolved goal at present. Overall, these studies portray advances as well as limitations in the effort to decipher protein recognition mechanisms and utilize the wisdom gained for mechanism-based antagonist design in an increasingly high throughput world stimulated by the advent of genomics and proteomics.

11:15 Combinatorial Lead Discovery of Antimicrobial Oxazolidinones
Dr. Gary W. Luehr, Senior Scientist II, Versicor, Inc.
Combinatorial chemistry is an essential drug discovery tool that offers unique opportunities for rapid lead discovery and optimization of bioactive molecules. Oxazolidinones are a new class of totally synthetic antibiotics active against a wide range of multidrug resistant pathogens. Recent approval of the first drug of this class linezolid (Zyvox®) has sparked further interest in the development of novel antibiotics of this structural type. As part of the Versicor's infectious disease program, we have applied combinatorial strategies for discovery and optimization of antimicrobial oxazolidinone structures. Several novel solid-phase methodologies to explore specific structural variations in oxazolidinone lead series have been developed. Recent examples of the novel lead structures identified through combichem and high-throughput screening will be described. Biological evaluation data highlighting the in vitro and in vivo activities of these novel molecules will also be presented.

11:45 From Target Family Directed Library To Target Specific Dedicated Library:A Winning Approach In Drug Discovery
Dr. Jacques Mauger, Research Scientist, Selectide, Aventis Pharma
High Throughput Synthesis is now well established as a powerful tool for hit discovery and lead optimisation. Automation has now become essential to decrease the time in synthesis. This talk will focus on strategies for libraries of new compounds to shorten the time cycle in the drug discovery, the importance of target libraries for hit generation and their impact, increasing values of generated libraries by information rich structures and parallel approaches in medicinal chemistry.

12:15 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

2:00 Chairperson's Comments
Dr. Alexander Tropsha, Associate Professor and Director, Laboratory for Molecular Modeling, School of Pharmacy, University of North Carolina at Chapel Hill

2:05 Combinatorial Chemistry Informatics and Library Design for Integrated Lead Discovery in Pharmaceutical Research
Dr. Mark Hermsmeier, Senior Research Investigator, Bristol-Myers Squibb
Combinatorial chemistry as applied in the pharmaceutical industry requires new and innovative informatics solutions for an integrated process. The first step is to represent all the structures that can be made using combinatorial synthesis that can be done with the available reagents. The next step is to use library design algorithms to identify a subset that has predicted physiochemical and biological properties relevant to the screening assays. The third step is automated structure generation of a putative library for the synthesis planning software and compound registration. The fourth step involves viewing and analyzing the biological results of a combinatorial library for iterative design. Each of these steps will be discussed.

2:35 Predictive QSAR Modeling: Applications to Data Mining
Dr. Alexander Tropsha
Quantitative Structure-Activity Relationship (QSAR) modeling is one of the most efficient tools for data mining. This presentation will concentrate on novel and developing methodologies for variable selection QSAR. The main emphasis will be placed on new strategies aimed at increasing the predictive power of QSAR models by rational selection of compounds for training and test sets from a given data set. Applications of predictive QSAR modeling to drug design and discovery, as well as quantitative assessment of druglike properties (ADMET), will be discussed.

3:05 Practical Outcomes of Data Mining in-Vivo HTS Data
Dr. Kirk Simmons, Senior Research Associate, DuPont Crop Protection
This presentation will focus on a comparative study during which time the quantitative performance of several widely-used datamining algorithms (decision trees, neural networks, genetic algorithms) was evaluated. These evaluations used historical in-vivo HTS screening data for testing and validating the performance of each method. In addition, some of the models generated during these studies were used to drive a compound acquisition campaign and the testing results for these purchases will be discussed in light of the historical screening hit-rates.

4:15 WaveScreen: A Novel Approach for Drug Discovery
Dr. David Spellmeyer, Chief Scientific Officer and Vice President, Drug Discovery, Signature BioScience, Inc.
Signature's drug discovery strategy is to evaluate potential new targets and compounds in parallel and screen for specific physiologic activity at the earliest points in the discovery process. The manifestation of this strategy is WaveScreen™, our novel parallel target and compound selection platform. The WaveScreen architecture integrates our proprietary spectroscopy technology, MCS, with assays and chemistries to allow direct access to a wide range of biologic activities. At the molecular level, proteins and their interactions are characterized by structure and conformation, by interaction with small molecules and other proteins, and by the products of activity in biochemical pathways and signal mediation. At the cellular level, cell-signaling activities are directly monitored via the cell's physiological response, rather than artificial constructs such as fluorescent dyes and reporters. We believe this new approach provides a complete and representative portrait of small molecule activity in a diversity of environments most closely resembling native and/or diseased states. An example of how WaveScreen has been applied to the drug discovery process will be illustrated.

4:45 Accurate Prediction of Aqueous Solubility
Dr. Daria Jouravleva, Technical Marketing Specialist, Advanced Chemistry Development, Inc.
Accurate prediction of aqueous solubility has been a long-sought-after goal among computational chemists because of the importance of solubility drug discovery: knowledge of a compound's solubility is essential for practical experimental reasons and to assess the possibility of passive gastrointestinal absorption. This talk will focus on the physical chemistry of the process of dissolving and describe the methods used at Advanced Chemistry Development to produce a global predictive method for the accurate prediction of aqueous solubility. Finally, a software product will be described that makes this prediction technology available to every medicinal chemistry in a simple and intuitive user interface or through your company's informatics infrastructure.

5:15 Automated Solid-phase Wittig Olefination Reactions
Dr. Walter Cristofoli, Application Scientist, Advanced ChemTech
The alkene functionality can be realized through variety chemical pathways. Olefin formation reactions have been a mainstay of organic reactions throughout it evolution, and continue to grow and progress through its inclusion in solid phase chemistry. Having had success in the initial stages, a variety of stereoselective bond-forming methodologies have been introduced. Utilizing both standard solid-phase support resins as well as polymer bound ylides to form small, multi-component libraries as well as novel compounds. Variations of the standard solution-phase methodologies are advantageous from the standpoint that solid-phase attachment allows for easy removal of the inorganic-containing by products, thus giving high yielding reactions under mild conditions. The formation of an alkene through a Wittig and related processes in and of themselves does not constitute an asymmetric process. If, however, the Wittig reagent is chiral, the reaction may become acceptably enantioselective. In this presentation, our findings and results will be presented.

5:45 Design of Drug-Like Combinatorial Libraries - An Application of Constrained Diversity
Dr. Eric A. Jamois, Product Manager, Computational Chemistry Applications, Accelrys Inc.
The design of combinatorial libraries has evolved from considering only diversity criteria to incorporating important "drug-like" characteristics. We will illustrate through several examples that incorporating such considerations only has a minimal impact on the diversity of the proposed libraries. So obtaining libraries which are both diverse and "drug-like" is indeed possible. In this fashion, selections can be biased towards molecules obeying a set of rules, such as the Lipinski rule of five or following more complex ADME models.

TRAVEL INFORMATION
Special Airline Discounts Available
Special zone and discount fares have been established on United Airlines for this conference. Please call United Airlines Meeting Reservations Center directly at 800-521-4041. You must reference ID #579YS.

HOTEL INFORMATION
Hilton San Diego Resort
1775 East Mission Bay Drive, San Diego, CA 92109
T: 619-276-4010 o F: 619-275-8944
Room Rate: $195 S/D
Cut-off Date: January 21, 2002
Please call the hotel directly to make your room reservation. Identify yourself as a Cambridge Healthtech Institute conference attendee to receive the reduced room rate. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.

CALL FOR EXHIBITORS
This meeting will focus on the newest techniques and technologies available for designing intelligent combinatorial libraries. Last year, at least 250 attendees consisting of scientific researchers, executives, managers and lab directors from pharmaceutical and biotechnology industries, as well as academic and research institutes attended the exhibit hall. Companies with services or products related to library design and screening for lead identification and small molecule lead identification, computational library design, drug discovery, and chemoinformatics will greatly benefit by sponsoring or exhibiting at this event. Please contact John Rodolewicz at 781-972-5452 for more information or to reserve a booth. Registrations received by October 26, 2001 can save your company up to $750!

CALL FOR POSTERS
Cambridge Healthtech Institute encourages attendees to gain further exposure by presenting their work in the poster sessions. Please fill out the registration form, with the poster title and primary author. To ensure inclusion in the conference binder, a one-page summary must be submitted and registration must be paid in full by January 11, 2002. Click here for poster instructions