CHI's Structure-Based Drug Design

Structure-Based Drug Design is based on a firm understanding of molecular recognition between active site groups and interacting molecules and is a strategy that has become an integral part of modern drug discovery. For the past ten years, combinatorial chemistry and diversity-based high-throughput screening were the approaches of choice for lead identification while computational methods were employed predominantly in lead optimization activities. Due to the recent volume and pace at which the 3-D structures of protein targets and their co-crystals have been made available, coupled with advances in computation tools, Structure-Based Drug Design has become a tool for lead generation as well as for optimization. Computational approaches to lead identification and design show many advantages over diversity-based, high-throughput screening, including reduced reagent storage and handling of large libraries, lowering of false positives often associated with HTS, and the ability to find low-molecular-weight leads even when HTS fails. However, there is little doubt that the greatest advances in drug discovery will be achieved by combining the strengths of computational and combinatorial chemistry/HTS strategies. This conference will cover the latest advances in Structure-Based Drug Design methodologies including flexible, faster docking techniques, virtual screening and library design, and target/structure focused combinatorial chemistry and will highlight specific gene-to-lead, preclinical, and clinical case examples. Anyone interested in advancing Structure-Based Design as a tool for drug discovery should attend this event.

Advisors
Dr. David Bailey, De Novo Pharmaceuticals Ltd.
Dr. Christian Lemmen, BioSolveIT GmbH
Dr. Mark Murcko, Vertex Pharmaceuticals Inc.
Dr. Tomi K. Sawyer, Ariad Pharmaceuticals, Inc.
Dr. Brian Shoichet, Northwestern University

Session Chairs
Dr. David Bailey, De Novo Pharmaceuticals Ltd.
Dr. Harren Jhoti, Astex Technology Ltd.
Dr. Christian Lemmen, BioSolveIT GmbH
Dr. Tomi K. Sawyer, Ariad Pharmaceuticals, Inc.

Additional Speakers
Dr. M. Amin Arnaout, Massachusetts General Hospital, Harvard Medical School
Dr. Richard D. Beger, U.S. Food and Drug Administration
Dr. Robin Carr, Astex Technology Ltd.
Dr. Holger Claussen, BioSolveIT GmbH
Dr. Andrea G. Cochran, Genentech, Inc.
Dr. Philip M. Dean, De Novo Pharmaceuticals Ltd.
Dr. Thompson N. Doman, Pharmacia Corporation
Dr. William J. Egan, Vertex Pharmaceuticals Inc.
Dr. Erik Evensen, Deltagen Research Labs
Dr. Leo Grinius, Procter & Gamble Pharmaceuticals
Dr. Sven Grueneberg, Aventis Pharma Deutschland GmbH
Dr. Philip J. Hajduk, Abbott Laboratories
Dr. Thomas L. James,University of California, San Francisco
Dr. Leslie A. Kuhn, Michigan State University
Dr. Steven LaPlante, Boehringer Ingelheim (Canada) Ltd.
Dr. Paul D. Lyne, AstraZeneca R&D
Dr. Chester A. Metcalf III, Ariad Pharmaceuticals, Inc.
Dr. Peter Nollert, Emerald BioStructures / deCODE Genetics
Dr. Santosh Putta, Bristol-Myers Squibb Pharmaceuticals Research Laboratories
Dr. Brian Raimundo, Sunesis Pharmaceuticals, Inc.
Dr. Eugene Shakhnovitch, Harvard University
Dr. Corey Strickland, Schering-Plough Research Institute
Dr. Chris Williams, Chemical Computing Group Inc.
Dr. Daniel F. Wyss, Schering-Plough Research Institute

Target Structures, 3-D Models, and Design
Crystallographic Studies of Integrins
In Cubo Membrane Protein Crystallization
Structure-Based Design of Inhibitors of the Hepatitis C Virus
NMR-Based Approaches for Lead Discovery
Drug Discovery Using a Fragment-Based Approach
Quantitative 13C NMR Spectrometric Data-Activity Relationships

Comparing a Variety of Tools in Structure-Based Drug Design
Guiding Molecular Design Efforts
Drug Discovery beyond High-Throughput Screening
Integrated Drug Discovery Approaches to Protein Kinase Inhibitors
Structural Characterization of Farnesyl Protein Transferase Inhibitors
The Role of High-Throughput X-ray Crystallography
A Novel Method for Molecular Subshape Similarity Matching

Ligand-Target Docking for Virtual Screening
Virtual Screening: The Good, the Bad, and the Ugly
Molecular Docking and HTS
Modeling Protein Flexibility
Successful Virtual Screening for Novel Inhibitors
Docking Flexible Ligands into Flexible Protein Structures
Three-dimensional RNA Structure-Based Drug Discovery
Large Scale Conformational Search

De Novo Library Design
Mapping and Analysis of Protein-Binding Epitopes
Integrating de Novo Ligand- and Structure-Based Drug Design
Focused Combinatorial Chemistry in Silico
Structured Peptides from Phage-Displayed Libraries
Comparing Structure-Based and Ligand-Based Approaches

7:00am Registration, Poster and Exhibit Viewing, and Light Continental Breakfast

8:00 Chairperson's Opening Comments
Dr. David Bailey, Chief Executive Officer, De Novo Pharmaceuticals Ltd.

8:10 Crystallographic Studies of Integrins
Dr. M. Amin Arnaout, Chief, Renal Unit, Massachusetts General Hospital; and Professor of Medicine, Harvard Medical School
Integrins are heterodimeric cell adhesion receptors involved in many physiologic processes such as cell migration, proliferation, and differentiation. Integrin affinity to ligands is regulated by inside-out signals; ligand binding in turn triggers outside-in signals that modulate cell behavior. The structural basis of affinity regulation and bi-directional signaling in integrins will be discussed.

8:40 In Cubo Membrane Protein Crystallization
Dr. Peter Nollert, Emerald BioStructures / deCODE Genetics
Only a small number of high-resolution structures of membrane proteins are available because this protein class is difficult to obtain and to crystallize. A new crystallization method, employing lipidic cubic phases, has been developed to improve this situation. Recent technological advances of this methodology will be presented as well as its successful application to the crystallization and the subsequent X-ray crystallographic structure determination of three different heptahelical bacterial membrane proteins.

9:10 Structure-Based Design of Inhibitors of the Critical Serine Protease of the Hepatitis C Virus
Dr. Steven LaPlante, Research Scientist, Boehringer Ingelheim (Canada) Ltd.
Structure - and dynamics based methods certainly have an important role to play in rational drug design. In particular, timely strategies that focus on the properties of the free and bound states of inhibitors are critical for coordinating efforts with medicinal chemists. Various examples and applications will be discussed that involve inhibitors of the critical serine protease of the hepatitis C virus (NS3 protease domain). The strategies include elucidating binding modes, identifying differences between the free and bound structures and dynamics, distinguishing the important and nonessential segments for binding, and probing for new or additional binding pockets on the target macromolecule.

10:15 NMR-Based Approaches for Lead Discovery
Dr. Daniel F. Wyss, Section Leader, Macromolecular NMR, Structural Chemistry, Schering-Plough Research Institute
High-throughput screening of large libraries of chemical compounds and natural products cannot always identify suitable leads. We have been using NMR-based screening techniques to identify druglike small molecule leads from customized libraries, which subsequently can be optimized through chemistry approaches. NMR-based screening has been useful in identifying novel scaffolds, which subsequently were linked, optimized by the parallel synthesis of a large number of analogs, or used as templates for structure-based inhibitor design. In addition, we have been using NMR together with X-ray crystallography to evaluate the binding of existing leads and their analogs for lead optimization. Our experience in applying different NMR approaches in the discovery and optimization of leads on several drug targets will be described.

10:45 Drug Discovery Using a Fragment-Based Approach
Dr. Brian Raimundo, Project Leader, Sunesis Pharmaceuticals, Inc.
Sunesis has developed an approach to small molecule inhibitor discovery that relies upon the identification and characterization of molecular fragments. These techniques have been applied successfully to the discovery of small molecules that inhibit protein:protein interactions. This presentation will discuss our fragment-based technology and its applications.

11:15 Quantitative 13C NMR Spectrometric Data-Activity Relationships Modeling
Dr. Richard D. Beger, Staff Scientist, Division of Chemistry, National Center for Toxicological Research, U.S. Food and Drug Administration
Methods are disclosed for establishing a quantitative relationship between 13C NMR spectral data of molecules and their biological binding activity. All the quantitative spectral data-activity relationship (QSDAR) models yield a relationship that may be used to predict the binding activity of a molecule from its experimental or simulated spectral data alone. We use three techniques to produce the QSDAR models. The modeling techniques are comparative spectral analysis (CoSA) of unassigned simulated 1D 13C NMR data, comparative structurally assigned spectral analysis (CoSASA) of simulated 13C NMR on backbone templates, and comparative structural connectivity spectra analysis (CoSCSA). CoSCSA modeling uses predicted 2D 13C-13C COSY for through-bond connectivity structural information combined with a theoretical 2D 13C-13C distance connectivity spectra for through-space distance selected structural information to produce a relationship among the 2-D spectral patterns and biological binding activity. QSDAR models for two biological endpoints are presented that demonstrate that the CoSCSA models always had a much better leave-one-out (LOO) q2 than the quantitative structure-activity relationship (QSAR) like COSASA models.

11:45 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

1:30 Chairperson's Comments
Dr. Harren Jhoti, Founder and Chief Scientific Officer, Astex Technology Ltd.

1:35 Guiding Molecular Design Efforts towards More Druglike Molecules
Dr. William J. Egan, Staff Investigator, Vertex Pharmaceuticals Inc.
Rational or random approaches to drug discovery, such as structure-based design and combinatorial chemistry/HTS, provide biologically active molecules. However, any molecule so produced must be suitable for clinical development. Thus, general druglikeness and good, specific ADMET properties are critically important. We will discuss approaches taken at Vertex Pharmaceuticals to assess and improve molecular druglikeness and ADMET properties.

2:05 Drug Discovery beyond High-Throughput Screening: A Case Study
Dr. Leo Grinius, Project Leader, Anti-infectives, Procter & Gamble Pharmaceuticals
High-throughput screening (HTS) is being used industrywide to identify active compounds in collections or libraries as quickly as possible and with high statistical accuracy. The HTS against a protein target using an accurate assay is expected to identify some interesting compounds among HTS hits that can be used as initial leads in drug development. But success in HTS depends on a number of factors that cannot always be controlled. For instance, compounds eventually decompose, especially if they are kept in a liquid format, while some compounds decompose faster than others. Moreover, some HTS hits have poor physical-chemical properties for use as potential leads. In such cases, it is often not clear whether the poor properties of HTS hits are defined by properties of the library or by the properties of the protein target itself. We think that the quality of hits can be improved by using virtual screening in conjunction with HTS. Virtual screening is based on the docking of large numbers of structures into a target's active site using computational methods. This approach is currently applied less frequently because it requires knowledge of the target's structure. It also depends to a large degree on the accuracy of virtual libraries of structures and the accuracy of computational methods as well. On the other hand, it has a number of advantages as compared to HTS. In this presentation, we will discuss results obtained using both HTS and virtual screening to identify hits for bacterial signal peptidase.

2:35 Integrated Drug Discovery Approaches to Protein Kinase Inhibitors
Dr. Chester A. Metcalf III, Principal Scientist and Combinatorial Chemistry Group Leader, Ariad Pharmaceuticals, Inc.
In the search for new therapeutic targets, protein kinases provide intriguing and promising opportunities for drug discovery. A multitude of ATP-based scaffolds have been used in the design of protein kinase inhibitors, relying on both structure-based and combinatorial methods for lead compound generation and optimization toward their respective biological targets. This presentation will review our ongoing efforts to develop small-molecule kinase inhibitors targeting either noncatalytic or catalytic domains of Src kinase using structure-based drug design, virtual screening, cheminformatics, and parallel synthetic methods. This work has resulted in the identification of low nM potent Src inhibitors for both cancer and bone disease.

3:45 Structural Characterization of Farnesyl Protein Transferase Inhibitors
Dr. Corey Strickland, Principal Scientist, Schering-Plough Research Institute
Farnesyl protein transferase (FPT) inhibitors as anticancer agents have advanced to clinical trials. In vitro and cell-based assays indicate that these molecules inhibit post-translational modification of ras to inactivate this oncogenic protein. Although clinical candidates differ dramatically in chemical structure, all are competitive with the ras protein. Here we will compare the X-ray crystallographically determined binding modes of FPT inhibitors currently in the clinic and show the unique interactions within the FPT active site made by the inhibitors. In addition, discovery of second-generation tricyclic inhibitors exhibiting nearly 100-fold greater inhibitor constants than the current clinical candidate SCH66336 (IC50 1.9 nM) will be described. Finally, the crystallographic structures of ras competitive inhibitors and ras-derived peptide substrates will be compared. Taken together, the comparative structural studies reveal a remarkable structural diversity in molecules that bind FPT with high affinity.

4:15 The Role of High-Throughput X-ray Crystallography Compared to High-Throughput Screening in Modern Lead Discovery
Dr. Robin Carr, Vice President, Drug Discovery, Astex Technology Ltd.
The discovery of novel drug leads at Astex Technology is driven by the company's unique structural screening approach to lead discovery, which utilizes protein crystal structures to detect the binding of small-molecule fragments. Using high-capacity virtual screening, fragmentation of known drugs, and ligands for related targets, many hundreds (to potentially thousands) of fragments are identified and prioritized for structural screening using the company's proprietary X-ray crystallography technologies. Coupling virtual screening with structural screening allows both the routine identification of efficiently binding fragments and their optimization and is rapidly iterated using library enumeration and high-capacity protein-fragment structures. This informatics-based approach results in a powerful process for rapid structure-based lead generation. The presentation will discuss the use of these approaches for rapid identification of lead compounds against kinase and phosphatase targets. In addition, the presentation will look to compare the strengths and weaknesses of this structure-based approach relative to high-throughput screening.

4:45 A Novel Method for Molecular Subshape Similarity Matching
Dr. Santosh Putta, Senior Research Scientist, Bristol-Myers Squibb Pharmaceuticals Research Laboratories
Molecules with similar shapes and features often have similar biological activity. Several computational approaches search chemical databases for new leads or templates based on overall molecular shape similarity. Active molecules often present critical subshapes that are required for binding, which may be missed by comparing overall shape similarity. We present a new approach to calculate subshape similarity and discuss its applications to structure-based drug design.

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

8:30 Chairperson's Comments
Dr. Christian Lemmen, President and Chief Executive Officer, BioSolveIT GmbH

8:35 Virtual Screening: The Good, the Bad, and the Ugly
Dr. Paul D. Lyne, Principal Scientist, EST Chemical Computing Group, AstraZeneca R&D
Virtual screening is becoming an increasingly popular technique in the pharmaceutical industry for the identification of leads in the drug discovery process. This popularity has resulted in an increase in the tools available for performing virtual screening. These include both structure-based and ligand-based approaches and span the range of biophysical-based, empirical-based, and shape-based approaches. The results of an evaluation of many virtual screening approaches (both structure-based and ligand-based) against several targets will be presented, and an assessment of the current state of the art will be made.

9:05 Molecular Docking and HTS in the Search for Novel Inhibitors of PTP1B
Dr. Thompson M. Doman, Senior Scientist, Pharmacia Corporation
In collaboration with Northwestern University we employed docking methods to prioritize compounds from the Available Chemicals Directory for testing as protein tyrosine phosphatase 1B inhibitors. Of 365 compounds purchased, 127 were active with an IC50 of 100 uM or less, a hit rate of 34.8%. We will describe these results as well as the results of a high-throughput screen that was also conducted for PTP1B, and we will show that the results for docking compared extremely favorably with HTS, in terms of hit rate as well as the quality of the hits.

9:35 Modeling Protein Flexibility in High-Throughput Computational Screening and Docking
Dr. Leslie A. Kuhn, Associate Professor of Biochemistry and Molecular Biology and Adjunct Associate Professor of Physics and Astronomy, Department of Biochemistry, Michigan State University
Flexibility modeling in virtual screening has typically focused on the ligand candidates. Our SLIDE tool balances ligand and protein side-chain flexibility and is fast enough to screen 100,000 molecules in one to a few days. Recent work on SLIDE has focused on improving its docking and scoring and incorporating knowledge of significant main-chain flexibility through coupling with our FIRST tool for protein and ligand flexibility modeling.

10:45 Successful Virtual Screening for Novel Inhibitors of Human Carbonic Anhydrase II
Dr. Sven Grueneberg, Research Scientist, Chemistry/Molecular Modeling, Aventis Pharma Deutschland GmbH
A new strategy is presented to search for possible leads of human carbonic anhydrase II. A protocol of several consecutive hierarchical filters, including several affinity prediction tools and as a final filter visual inspection, has been applied to score the obtained hits. A set of these virtually identified hits was profiled in an enzymatic in vitro assay; one compound showed activity in the micromolar, one in the nanomolar, and three in the subnanomolar range. X-ray structure determinations of the complexes with two of the most potent ligands were performed to confirm their binding modes predicted by molecular docking.

11:15 Docking Flexible Ligands into Flexible Protein Structures
Dr. Holger Claussen, Senior Research Scientist, BioSolveIT GmbH
The enzyme aldose reductase (AR) is believed to play an important role in the development of severe degenerative complications of diabetes mellitus. Therefore AR is a potential target for drug design. Since AR has a highly flexible active site it can bind to very different ligands. Although side-chain or even backbone adjustments upon ligand binding are also frequently observed in other proteins, only very few discrete molecular docking approaches take this protein flexibility at least to some extent into account. Full protein flexibility can currently only be handled by time-consuming simulation approaches. We present the new software tool FLEXE that addresses the problem of protein flexibility during docking calculations. FLEXE can dock flexible ligands into flexible proteins that are represented by an ensemble of structures. On average FLEXE takes about five and a half minutes for placing one ligand on a common day workstation. On our target system aldose reductase FLEXE is able to reproduce the correct binding modes of different ligands that cause major conformational changes within the active site of the enzyme upon binding.

11:45 Three-dimensional RNA Structure-Based Drug Discovery
Dr. Thomas L. James,Chairman, Department of Pharmaceutical Chemistry University of California, San Francisco
RNA molecules can possess a degree of structural complexity and functional diversity approaching that of proteins. We have developed a method suitable for computational screening of a large chemical library (e.g., 200,000 compounds) to identify non-nucleotide, nonpeptide organic molecules to bind to RNA targets. Using HIV-1 TAR RNA as a target, we have screened the Available Chemicals Directory and identified several small molecular weight compounds that were subsequently found in experimental assays to bind HIV-1 TAR and completely inhibit, at concentrations of 100 nM, its interaction with equimolar HIV-1 Tat protein and inhibited Tat transactivation in cells. The structure of one compound bound to TAR RNA has been determined via NMR that largely supports the predicted structure.

12:15 High-Throughput Conformational Search
Dr. Chris Williams, Director of ScientificSupport, Chemical Computing Group Inc.
A methodology is presented for conformational search of large collections of drug-sized molecules. The method is based upon the subdivision of molecules into fragments, the conformational search of the fragments and the assembly of the fragment conformations into molecular conformations. Applications to diverse collections and to combinatorial libraries are presented along with timings.

12:45 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

2:30 Chairperson's Comments
Dr. Tomi K. Sawyer, Vice President, Ariad Pharmaceuticals, Inc.

2:35 Rational Design of Compounds with Reduced Affinity for Human Serum Albumin
Dr. Philip J. Hajduk, Group Leader, NMR-Based Screening, Abbott Laboratories
Many lead compounds bind to serum albumin and exhibit markedly reduced efficacy in vivo as compared to their potency in vitro. Traditional
approaches to reducing albumin binding involve medicinal chemistry efforts to place substituents at tolerated positions on the lead molecule, with no
knowledge as to whether these modifications would be expected to disrupt binding to serum albumin. This talk will describe a structure-based strategy
for designing compounds with reduced affinity for albumin, in which structures of the lead compound in complex with both the target protein and domain-3 of
human serum albumin are obtained. This structural data allows the design of modifications that would not be expected to disrupt binding to the target, but
would likely reduce albumin binding.

3:05 Integrating de Novo Ligand- and Structure-Based Drug Design: Fundamental Problems and Possible Solutions
Dr. Philip M. Dean, Chief Scientific Officer, De Novo Pharmaceuticals Ltd.
The pharmacophore hypothesis has been of great value for drug design and development. The principal issue in the pharmacophore hypothesis arises from data reduction of complex molecular and spatial information from a set of active molecules to a defined number of points. The presentation will compare the problems associated with ligand- and structure-based design using de novo design methods. Attention will focus on ligand-point site-point definition, dynamic problems of site points in flexible sites, molecular partial similarity, combinatorial problems of strategy selection for design, and reduction to practice.

3:35 Focused Combinatorial Chemistry in Silico: SMoG Algorithm and Its Use to Design Novel Picomolar Inhibitor for a Known Enzyme
Dr. Eugene Shakhnovitch, Department of Chemistry and Chemical Biology, Harvard University
In my talk I will present SMoG-a highly versatile, fast, and accurate algorithm to design small-molecule ligands for proteins of known structure. The statistical-mechanical derivation of highly accurate knowledge-based scoring function will be presented, as well as an example of a successful application of SMoG where it was used to design novel ligand for carbonic anhydrase with record potency of 30pm dissociation constant. The use of SMoG and other computational approaches to drug discovery will be further discussed.

4:35 Structured Peptide Ligands from Phage-Displayed Libraries: Prospects and New Strategies
Dr. Andrea G. Cochran, Scientist, Department of Protein Engineering, Genentech, Inc.
Display of highly diverse, unbiased (näive) peptide libraries on bacteriophage has emerged as a powerful technology for the discovery of novel peptide ligands. Surprisingly often, phage-derived peptides adopt compact structures when bound to protein targets, or even when free in solution. We have used this information to help determine those peptide features necessary for binding and to evaluate the likelihood of converting these peptides into smaller peptidomimetics or small-molecule leads. In a complementary strategy, we are exploring very small structured peptide scaffolds (b-hairpins) for use as phage display platforms. The intention is to use phage-display to discover peptides with focused binding determinants that could be transferred in a straightforward way to nonpeptide platforms (e.g., small-molecule turn mimetics).

5:05 Comparing the Performance of Structure-Based and Ligand-Based Approaches to Library Design
Dr. Erik Evensen, Senior Research Scientist, Deltagen Research Labs
In selecting and applying computational tools for combinatorial library design it is necessary to understand the performance and limitations of the available methods. In an iterative, integrated drug discovery setting computational tools are used to help guide follow-up efforts. Therefore, it is important to know to what extent compounds selected for screening provide the data required to refine the selection criteria for successive rounds of synthesis. It is even more critical to assess how the selection method, as part of the drug discovery cycle, capitalizes on such data. To address these questions, we present the methods for performing these comparisons and report the results of evaluating a variety of descriptors and strategies (both commercial and internally developed and derived from structures and ligands) for selecting compounds and following up on experimental results.

5:35 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

Premier Sponsor

De Novo Pharmaceuticals is a dynamic, well-funded drug discovery company based in Cambridge, UK. Using our world-leading proprietary software platforms we are creating and reducing to practice novel, patentable, molecules as candidates for drug development against both enzyme and receptor based targets. We also offer a complete design service encompassing both structure-based and ligand-based design when no structural data is available. Our services are available either through drug design partnerships or through lead licensing opportunities.
Corporate Sponsor

Astex Technology is a structure-based drug discovery company pioneering the use of high throughput X-ray crystallography (HTX™) for the rapid identification of novel drug candidates. The company's unique structural screening approach couples in silico and x-ray crystallographic screening technologies; this is applied to detection and optimization of candidate drug compounds and small-molecule fragments against key proprietary and public domain protein targets.
Corporate Sponsor

CCG provides state of the art discovery software for pharmaceutical and biotech research. MOE - the Molecular Operating Environment, is a new generation of chemical computing software designed around a high performance language, Scientific Vector Language (SVL). MOE's built-in computational application covers High Throughput Discovery; Structure Based-Design, Protein & Homology Modeling; Modeling & Simulation, and Corporate Deployment and Methods Development. With our proprietary technology, researchers have the flexibility to choose the computing platform they wish, running on HP UNIX, SGI, Sun, Linux, WinNT, Win95-2000. MOE is an ideal tool for corporate deployment and is accessible via a variety of access modes (GUI, Batch, Web), providing a streamlined environment accessible to researchers enterprise wide.
Related Genomic Report:
High-Throughput Genomics
This report reviews leading companies' approaches to gene sequencing and the increasing availability of high-throughput methods for studying the proteins they encode, and the pathways in which they are involved. Don't miss this opportunity to gain insight from over 20 companies on their specific approaches and technologies. Conference Special! Register for the conference and purchase this report with a 20% discount!!! Prices: $1875 for print version, $2875 for single-user electronic version and $5625 for enterprisewide electronic version (includes two print copies) For details on this and all CHI reports, visit www.chireports.com or contact Vernette Roach at 781-972-5438.

Hotel Information
The Marriott Cambridge Hotel
Two Cambidge Center
Cambridge, MA 02142
T: 617-494-6600
F: 617-494-0036
Room Rate: $195 S/D
Cut-off Date: March 26, 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.

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.

Call for Sponsorship and Exhibit Opportunities
Some of the most interesting advancements in the drug discovery process have been made through the implementation of structure-based drug design principles. Certainly its functionality is maximized when used in conjunction with the mainstay techniques of drug discovery such as library screening, combinatorial chemistry, and high-throughput screening. By providing specific gene-to-lead examples, this conference will discuss the latest improvements in docking techniques, virtual screening, and target-structure-based combi-chem. We strongly encourage any company with services or products related to HT-crystallography, NMR, mass spec, lead identification, databases and libraries, structure-based drug design, docking strategies, QSAR, virtual screening, rational drug design, drug discovery, and combinatorial chemistry to consider sponsoring or exhibiting at this event. Certainly sponsorship is the best way to prominently elevate your company's presence and influence at this conference. Although exhibit space can be purchased separately, many sponsorship packages will include a booth. For more information on sponsorship opportunities or to reserve a booth, please contact Angela Parsons at 781-972-5467 or aparsons@healthtech.com.

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 CD, a one-page summary must be submitted and registration must be paid in full by March 15, 2002. Click here for poster instructions

5:45-7:00 Reception (sponsored by Chemical Computing Group, Inc.)