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Cambridge Healthtech Institute’s 6th Annual

• Pre-Conference Short Course: Designing Structure-Based Kinase Inhibitors

• Cutting-Edge Sessions from Industry Leaders

• Hot Topic Sessions on Fragment-Based Drug Discovery

• Panel Discussion: How Much More Effective will Drug Discovery Become in the Next 10 Years?

• Case Studies from Abbott Laboratories and Wyeth Research

• And much more!

• Peter Fedichev, Ph.D., Corporate Scientific Officer, Quantum Pharmaceuticals

• William L. Jorgensen, Ph.D., Whitehead Professor of Chemistry, Department of Chemistry, Yale University

• Dr. Mario Lobell, Computational Chemistry, Bayer HealthCare, Germany

• Klaus Müller, Ph.D., Pharmaceutical Research-Head of Science & Technology Relations, F. Hoffmann-La Roche Ltd.

• Mark Murcko, Ph.D., Vice President and Chief Technology Officer, Vertex Pharmaceuticals, Inc.

• Christopher Murray, Ph.D., Director, Computational Chemistry and Informatics,Astex Therapeutics

• Leszek Poppe, Ph.D., Principle Scientist, Molecular Structure Department,Amgen, Inc.

• Tomi K. Sawyer, Ph.D., Senior Vice President, Drug Discovery, ARIAD Pharmaceuticals

• Robert A. Volkmann, Ph.D., Senior Research Fellow, Pfizer Global Researchand Development

• And many more!

Register by March 24th & Save up to $350!

Lead Sponsoring Publication:Corporate Sponsors: Corporate Support:

Hear from Industry Leaders Including:

Conference Highlights:

June 14-16, 2006 • World Trade Center • Boston, Massachusetts

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SSttrruuccttuurree--Based Drug Design

Final Agenda

Cambridge Healthtech Institute1037 Chestnut Street, Newton Upper Falls, MA 02464T: 617-630-1300 or toll-free in the U.S. 888-999-6288 • F: 617-630-1325 • www.healthtech.com

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Corporate Biographies

Founded in 1990, Schrödinger is widely recognized as a scientificleader in developing state-of-the-art chemical simulation software for use in pharmaceutical andbiotechnology research. The company's products range from general molecular modeling pro-grams to a full-featured suite of drug design software that uses both ligand- and structure-basedmethods.

Tripos partners with customers to increase their productivity and manageproduct pipeline attrition in order to bring viable drugs to market. Using knowledge-driven chem-istry and proprietary technologies to accelerate hit finding, hit-to-lead, and lead optimization,Tripos Discovery Research has reduced discovery timelines by up to 30%.

Dedicated Focus on Computational Kinase

12:30pm Pre-Conference Registration

1:40 Chairperson’s Opening Remarks

1:45 Selectivity of Kinase InhibitorsDr. Doris Hafenbradl, Director Biochemical Screening, GPC Biotech, Germany

This presentation will address different tools and technologies for the determination ofkinase inhibitor selectivity. It will be shown how critical it is to evaluate selectivity withsuitable data. The structural aspects of protein kinases determining the selectivity will alsobe highlighted. It will be discussed how selectivity data can be used within the lead find-ing and optimization processes.

2:15 Determinants of Selectivity in Targeting the JAKFamily of Kinases for Treatment of Cancer andInflammatory Disease

Dr. Andrew Wilks, Corporate Scientific Officer, R&D, Cytopia Research Pty, Ltd.,Australia

The JAK family of PTKs has four members in the human genome (JAK1, JAK2, JAK3 andTYK2) each of which plays an important role in the intracellular signaling downstream ofparticular cytokines. A single point mutation in the kinase like domain of JAK2 has recent-ly been linked to a significant proportion of cases of Myeloproliferative Disorders, includ-ing Polycythemia Vera (PCV) and Essential Thrombocytemia. Parallel computationalapproaches to molecular modeling, drug design and in silico screening are being explored togenerate potent and highly specific small molecule inhibitors of a number of the JAK fam-ily of PTKs. Co-crystallography of these potent and specific JAK inhibitors with the JAK2kinase domain provides important insights into the feasibility of generating drugs againstthese important targets.

2:45 Refreshment Break

3:15 In silico ADMET Traffic Lights and PhysChem Scoresand their Application to Kinase Inhibitors

Dr. Mario Lobell, Computational Chemistry, Bayer HealthCare, Germany

The need for in silico characterization of HTS hit structures as part of a data driven hitselection process is demonstrated. A solution is described in form of the in silico ADMETTraffic Light and PhysChem scoring system. The described in silico system has been extensively validated with Bayer in-house data, literature data anda collection of launched small molecule drugs. The system is applied to examples of kinaseinhibitor drugs and drug candidates.

3:45 Structural Basis for the Non-Competitive Inhibitionof Human MEK1

Dr. Jeffrey Ohren, Senior Scientist, Structural Biology Group, Department ofChemistry, Pfizer Global Research & Development

MAP kinase 1 (MEK1) plays an integral role in the formation, progression and survival oftumors, in addition to mediating many inflammatory processes. As a result, MEK1 repre-sents an attractive target for pharmacological intervention in both proliferative andinflammatory diseases. The recent X-ray structure of human MEK1 in a complex with ATPand a non-competitive, small molecule inhibitor provides structural insight into a uniquemode of kinase inhibition and may provide a platform for the structure-based design of thenext generation of protein kinase inhibitors.

4:15 Insights for Design: Differential Binding of Inhibitorsto Active and Inactive CDK2

Dr. Campbell McInnes, Head, Structure-Based Drug Group, Cyclacel Ltd., Scotland

The cyclin-dependent kinases (CDKs) are important anti-cancer targets and despite hav-ing been characterized in complex with a wide variety of inhibitors, the majority of CDK2structures solved are of the inactive enzyme. Crystallographic data exists for only one ATP-competitive inhibitor in both the active cyclin-bound and inactive CDK2 forms. We havesolved the structures of six inhibitors in both the monomeric CDK2 and binaryCDK2/cyclin A complexes and demonstrate for the first time that significant differences inbinding of CDK2 ligands occur depending on the activation state. The binding mode oftwo ligands varies substantially as a result of binding site differences induced upon CDK2activation. Furthermore, an energetic analysis of CDK2/cyclin complexes demonstratesthat a good correlation exists between the in vitro potency and calculated energies of inter-action, while indicating that no such relationship exists for monomeric CDK2-inhibitorstructures. These results confirm that structures solved in complex with the monomericCDK2 do not fully reflect the active conformation of bound inhibitors. This analysisreveals significant implications for inhibitor design towards active structures since these aredistinct from the inactive CDK2 and also suggests that the monomeric CDK2 conforma-tion could be selectively inhibited.

4:45 End of Short Course

4:45-5:30 Main Conference Early Registration

Showcase your companys expertise, brand your solutions and develop revenue-generating opportunities with qualified decision-mak-ers by exhibiting or sponsoring CHI's Structure-Based Drug Design. Sponsorship packages are designed to achieve your businessdevelopment and networking goals and objectives.

Sponsored Speaking Opportunities Include:• Breakfast or Luncheon Workshops, including podium time• Embedded Presentations within the conference

CHI managers will work closely with you to shape a package that suits your company's objectives and budget. Numerous promotional and sponsorship packages exist. Please contact Suzanne Carroll to discuss how to participate at 617-630-1352, oremail her at scarroll@healthtech.com

Sponsor and Exhibitor General Information

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Pre-Conference Short Course: Wednesday, June 14th Designing Structure-Based Kinase Inhibitors

Cover Image Courtesy of: ARIAD Pharmaceuticals and University of Basel/Biographics Laboratory 3R

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TTHHUURRSSDDAAYY,, JJUUNNEE 11557:30am Conference Registration, Morning Coffee, Exhibit

and Poster Set-Up

8:30 Chairperson's Opening Remarks

8:40 Progress in Computer-Aided Drug Design William L. Jorgensen, Ph.D., Whitehead Professor of Chemistry,Department of Chemistry, Yale University

General issues for structure-based drug design will be covered based on our experi-ences with molecule docking, growing, fragment simulations, ADME-properties eval-uation, similarity searching, and free-energy perturbation calculations. In-house drugdevelopment is being pursued through multiple computer-aided routes, followed bysynthesis, and assaying. (a) In one mode, the design begins with use of the ligand-growing program BOMB, which rapidly constructs combinatorial libraries given thestructure of the target protein and a selected core and substituents. BOMB grows theanalogs inside the protein's binding site, performs a thorough conformational search,and estimates the analog's binding affinity or activity using scoring functions. TheQikProp program is applied to filter all designed molecules to insure that they havedrug-like properties including solubility and cell permeability. MC/FEP simulationsare then performed to refine the predictions for the best scoring leads using hundredsof explicit water molecules and extensive sampling for the protein and ligand. (b)Alternatively, screening of known compound libraries is performed by filtering fordrug-likeness and similarity to known active compounds with QikProp and QikSim,followed by docking with Glide. (c) Lead compounds are also sought through multi-ple-copy simulations of small molecules (fragments) with BOSS. In this case a proteinis saturated with hundreds of copies of a fragment, which are then annealed to seekconsensus binding sites. Recent methodological advances and representative applica-tions will be presented with emphasis on inhibitor development for HIV reverse tran-scriptase.

10:10 Networking Coffee Break, Poster and ExhibitViewing

10:55 Combining Flexible Docking and MultidimensionalQSAR from Quantifying Binding Affinities to thePrediction of Adverse Drug Reactions

Markus Lill, Ph.D., Lecturer, Department of Pharmacy, University of Basel; ProjectLead, ADME Laboratory, Biographics Laboratory 3R

The quantification of ligand-binding affinities to a macromolecular target represents amajor challenge in computer-aided drug discovery. We present a new technology developedat our laboratory to identify and quantify binding modes for ligands of biomedical interest.It combines flexible docking at the target protein with a novel multidimensional QSARconcept (consensus scoring using Quasar [1,2] and Raptor [3]). In our approach, inducedprotein fit (receptor-to-ligand adaptation) is explicitly simulated. The technology has beenapplied to nuclear receptors [2,4] and cytochrome P450 [5] and demonstrates the ability to

predict the affinity for large and diverse ligand sets binding to a common target protein andsuggest a potential to predict adverse effects triggered by drugs and chemicals [6].

11:25 Case Study of Structure-Based Design for DPP-IVInhibition

Kenton Longenecker, Ph.D., Protein Crystallographer, Structural BiologyDepartment, Abbott Laboratories

Pharmaceutical inhibition of dipeptidyl peptidase IV (DPP-IV) is a recently exploredstrategy aimed to benefit patients with type-II diabetes by regulating plasma glucoselevels. X-ray crystallographic studies of DPP-IV in complex with inhibitors aideddrug candidate discovery through structure-based evaluation and design. This pres-entation will highlight contributions of structural biology to these efforts at AbbottLaboratories.

11:55 An Integrated Approach to Library Design W. Pat Walters, Ph.D., Senior Research Fellow, Computational Chemistry andMolecular Modeling, Vertex Pharmaceuticals, Inc.

A chemist designing a combinatorial library must consider many criteria when selectingreagents for synthesis. Factors such as target potency, physical properties, metabolic stabil-ity, and off-target activity are among many parameters that must be optimized. Althoughcomputational models exist to aid the chemist, these models are often poorly validated andare not easily integrated into the drug discovery process. As part of a continuing effort toprovide library design tools for medicinal chemists, we have created a software tool knownas MedChem2. This software provides an easy means of linking a virtual combinatoriallibrary with a well-validated set of computational models. The application of these modelscan dramatically reduce the size of a virtual library, and help to focus a chemistry effort onthe most relevant compounds. Models in MedChem2 are constructed using NOMAD, aninternally developed software platform that allows computational chemists to identify opti-mal combinations of molecular descriptors and machine learning methods. Models gener-ated using NOMAD can then be published to MedChem2 where they become part of themedicinal chemistry workflow. This presentation will provide an overview of NOMAD andMedChem2, as well as example applications of both programs.

12:25pm Lunch on Your Own (Technology Workshop Sponsorship Available)

1:35 Chairperson's Remarks

1:45 Biospectra Analysis: Model ProteomeCharacterizations for Linking Molecular Structureand Biological Response

Robert A. Volkmann, Ph.D., Senior Research Fellow, Pfizer Global Research andDevelopment

Establishing quantitative relationships between molecular structure and biological effectshas been a long-standing goal in drug discovery. An operationally simple probabilisticstructure-activity relationship (SAR) approach, termed biospectra analysis, which uses pat-tern similarity between biospectra of molecules as determinant, will be described.Comparison of biospectra derived from in vitro assays yields precise chemical structure infor-mation and is useful for identifying pharmacology and side effect similarities between med-icines. Specific examples will be provided.

2:15 Discovery of Ligands for Nurr1 by Combined Use ofNMR Screening with Different Isotopic and Spin-Labeling Strategies

Leszek Poppe, Ph.D., Principle Scientist, Molecular Structure Department, Amgen, Inc.

A comprehensive approach to target screening, hit validation and binding site determina-tion by nuclear magnetic resonance spectroscopy (NMR) is presented. Screening by 19FNMR signal perturbation, followed up by magnetization transfer experiments and second-site screening with spin-labeled ligand, led to discovery of a molecule which binds to theLigand Binding Domain of Nurr1 with dissociation constant ~ 20 uM. With the help ofuniform and residue specific 15N isotope labeling and derivatization of Cys residues with2-mercaptoethanol-1-13C we were able to determine the binding site location with knowl-edge of the APO coordinates.

2:45 Success and Lessons from 11 betaHSD1 HomologyModels: Using Models of Very Low Homology inDocking and Design

Ying-Duo Gao, Ph.D., Senior Research Fellow, Molecular Systems, Merck & Co. Inc.

11beta-hydroxysteroid dehydrogenase type1 (11beta-HSD1) is a potential target for treat-ment of some of the health problems associated with Metabolic Syndrome. In assistingmedicinal chemistry in lead optimization, we generated homology models of human andmouse 11betaHSD1 enzymes based on 17betaHSD1 and 7alphaHSD1 structures. Thesemodels were used extensively in the program. In this presentation we demonstrate thatmodels with very low homology (<25%), that may only partly present the active site cor-rectly, can be highly valuable for understanding SAR of the ligands and suggesting new

HOMOLOGY, MODELING, AND LIGAND-BASED DESIGN

EXPERIMENTAL APPROACHES

Reaping The Rewards of Fragment-Based Drug Design 9:10 Fragments to Clinic: Successful Applications

of Fragment-Based Drug DiscoveryChristopher Murray, Ph.D., Director, Computational Chemistry and Informatics,Astex Therapeutics

This presentation will focus on a structure-based approach to the design of potentinhibitors starting from weakly binding fragments. The discovery of cdk2 inhibitorswhich are currently in phase I clinical trials will be described. The talk will also outlinehow the approach was used to rapidly identify novel hsp90 inhibitors with good in vivoefficacy. There will be a discussion of fragment linking versus fragment growing strate-gies and the approaches will be compared for the serine proteases, thrombin andUrokinase.

9:40 Assembling Fragments into Molecules in Structure-Based Drug Design

Jeffrey Wiseman, Ph.D., Vice President and Officer, Technology & InformaticsDepartment, Locus Pharmaceuticals

Grand canonical ensembles provides a rapid way to calculate thermodynamically rigor-ous binding affinities for molecular fragments. Given this accurate scoring function, thetalk is about the state-of-the-art for the additional factors required in assembling frag-ments into molecules with predictable affinities: sampling efficiency, conformationalflexibility, additivity of fragment free energies, tightly bound water, and protein flexibil-ity. The ability to quantitatively predict tightly bound water, in particular, is found tobe essential in the accurate prediction of binding poses and energies.

PROTEIN-TARGETED DESIGN

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Mark Murcko, Ph.D.,Vice President and Chief Technology Officer, Vertex Pharmaceuticals, Inc.

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designs. In addition, the recently available crystal structures of human and mouse11betaHSD1 allowed us to assess the homology models and discuss how to improve thistype of modeling.

3:15 Technology Watch (Sponsorship Available)

Beyond Scoring Functions: Fast First-Principles Quantum andMolecular Physics Tools for Structure-Based Drug DesignKay Denis, MBA., Postion TBA, Timtec, Inc., Business Partner/distributor ofQuantum Pharmaceuticals; On behave Peter Fedichev, Ph.D., CSO,Quantum.Corporate Scientific Officer, Quantum Pharmaceuticals

Quantum is a computational platform aimed at direct pplications of powerful quantum andmolecular modeling structure based tools for fast and accurate predictions of protein-ligandbinding affinities. The ingredients are: a good, polarizable force field based on quantummechanics; a solvation energy model; and statistical physics for entropy change evaluation.The transferrability of the vacuum force field for aqueous calculations is ensured by itspolarizability and the quality of the water model, but not by the excessive parametrization.This ideology provides a solid and physically motivated ground for the free binding energycalculations. The software has been extensively tested against all available experimentaldata and has been recently released. Possible areas of application: High Throughput VirtualScreening, Computer Aided Drug Design, Cheminformatics, Computational Chemistryand Biology, ADMET prediction. An unprecedented level of accuracy together with a sim-ple and efficient user interface allows for in silico lead optimization. The technology isexpected to speed up pharma R&D radically and irrevocably change the computationalchemistry and drug discovery

3:30 Networking Refreshment Break, Poster and Exhibit Viewing

4:00 Docking Studies of A3 Agonists and AntagonistsSuggest Activation Mechanism of AdenosineReceptor

Soo-Kyung Kim, Ph.D., Senior Research Associate, Beckman Institute, MolecularSimulation Center, California Institute of Technology

To determine the different binding modes of agonist and antagonist to A3 adenosine recep-tor (AR), the docking studies of A3 selective nucleoside agonists and nucleoside/non-nucleoside antagonists were compared by using the FlexX and the FlexiDock automateddocking procedure. There are common binding regions for the exocyclic amino groups ofeach 9H-purine ring in agonist Cl-IB-MECA and the 1H-[1,2,4]triazolo[1,5-c]quinazolinering in non-nucleoside antagonist CGS15943 through H-bonding to the side chain ofN6.55. In addition, hydrophobic interactions of N6-aromatic group were overlapped, inter-acting with F168 in EL2. For binding domains of agonist, additional H-bonding of theribose 3'- and 5'-substituents with the hydrophilic amino acids T3.36, S7.42, and H7.43and hydrophobic interaction of the terminal methyl group of the 5&#61602;-uronamideinteracted with the hydrophobic side chain of F6.44 required for the characteristic side-chain movements of TM6 and TM7. Here we present the novel insights in the putativeactivation mechanism of A3AR. The fact that agonist binding disrupts the intramolecu-lar H-bonding network through W6.48 and H7.42 and occurs the rotation of TM6 suggeststhat these activation mechanisms might be extended to other members of the AR family.Collaboration with Kenneth A. Jacobson, Ph.D., Section Chief.

4:30 Bridging the Gap between Protein Cavities byVirtual Screening

Hans Briem, Ph.D., Senior Scientist, Compound Design and CompoundCharacterization/Computational Chemistry, Schering AG

One strategy to enhance the binding affinity of protein ligands is to identify sub-pockets onthe protein surface to which additional tether groups linked to a given scaffold may bind. Wewill demonstrate how we used the new module FlexxC-Pharm to efficiently dock large com-binatorial libraries while simultaneously considering user-defined pharmacophore constraints.This approach allows us to prioritize sets of virtual combinatorial libraries by their ability tobridge the gap between protein cavities of the target of interest.

5:00 Case Presentation of Strategies for High-Throughput Molecular Docking

Diane Joseph-McCarthy, Ph.D., Principal Research Scientist, Chemical andScreening Sciences Department, Wyeth Research

In structure-based design, molecular docking techniques are used to predict the bind-ing of a set of proposed compounds. Accurate molecular docking of small moleculesto a target structure requires adequate sampling and accurate scoring of each proposedligand in the target binding site. The use of our in house pharmacophore-based dock-ing approach on several therapeutic target projects will be presented and compared tothe use of commercial software. In addition, the exploration of the inclusion of proteinflexibility during docking will be discussed.

5:30-6:30 Networking Reception in the Exhibit Hall

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8:00am Morning Coffee (Sponsorship Available)

8:30 Chairperson's RemarksTomi K. Sawyer, Ph.D., Senior Vice President, Drug Discovery,ARIAD Pharmaceuticals

8:40 Structural and Functional Properties of OncogenicProtein Kinases that Manifest Resistance: Chemical Biology and Drug Design StrategiesTomi K. Sawyer, Ph.D.

Oncogenic protein kinases are key therapeutic targets for drug discovery. X-ray crys-tallographic, biochemical and cellular studies have revealed both structural and mech-anistic properties of several oncogenic protein kinases. In an increasing number of cases, resistance to inhibition has shown to involve criti-cal amino acid mutations in the ATP or proximate binding sites for small-moleculeinhibitors. These challenges are being addressed by both chemical biology and drugdesign strategies. A case example is T315I mutation of Bcr-Abl kinase.

9:10 Embracing Chemokines: Understanding Specificityand Selectivity of Chemokine Binding Proteins

João Dias, Ph.D., Post-doc, Chemistry, Serono Pharmaceutical Research Institute

Chemokines control the migration of leukocytes through interaction with receptors of theseven transmembrane G-protein coupled receptor family. Dysregulation of this systemresults in excessive cellular recruitment, with dramatic implications in inflammatory andautoimmune diseases. Blocking the receptor-chemokine interaction could thus have ther-apeutic value, since prevention of this directional migration represents an effective anti-inflammatory strategy. Nature provides efficient strategies, employed by some parasites andviruses, to elude the hosts’ immune system, and hence avoid an inflammatory response.Ticks can feed from several hours to days or even weeks, evading the host immune response(haemostatic, immune and inflammatory). Tick saliva components include enzymes,enzyme inhibitors, amine binding proteins and cytokine homologues. We have construct-ed a cDNA library from tick salivary glands, which was screened against severalchemokines. We have identified a new chemokine binding protein (ChBP) from tick sali-va, which binds to some selected chemokines, and does not share any relevant sequenceand structural homology to any other known and available protein. We have solved thecrystal structure of the human chemokine MIP-1-alpha in complex with this novel ChBP,and have hence unraveled the specific interactions between these two proteins. Upon com-plex formation, the N-terminal of the chemokine and the N-terminal and C-terminal ofthe ChBP are stabilized. The N-terminal of the chemokine plays a major role in this inter-action by forming the lid to the pocket that anchors tryptophan 89 from ChBP, whichinteracts tightly through an aromatic stacking with phenylalanine 29 from MIP-1-alpha.The integration of our current knowledge, combined with protein homology modeling andsite directed mutagenesis studies, will provide a consolidated platform for the generation ofstructure based drug designed chemokine inhibitors.

9:40 Numerical Indices and a Statistical Framework forStructure-Based Drug Design

Cele Abad-Zapatero, Ph.D., Associate Resident Fellow, R-46Y Department, Abbott Laboratories

Recently, the concept of ligand efficiency as a measure for lead selection was suggested(Hopkins et al., Drug Discovery Today, 2004, 9:430-431). A more comprehensive analysisof ligand efficiency indices will be presented, including the concepts of binding efficiencyand surface efficiency (Abad-Zapatero and Metz, Drug Discovery Today, 2005, 10:464-469)and their application to guide the process of drug discovery, and specifically its integrationinto the structure-based drug design methods to make them more efficient and numerical-ly robust.

10:10 Networking Coffee Break, Poster and Exhibit Viewing

10:55 The Dance of the Molecules: How to OptimizeLigand Alignments in Torsional Space

Robert D. Clark, Ph.D., Senior Director, Software Research Department,Tripos, Inc.

Pharmacophore models have traditionally been limited to features that must be shared byevery ligand that binds tightly to the target protein. Most also fail to take steric propertiesshared among the various known ligands into consideration. ALAHAD is a new fully flex-ible ligand alignment program that supports multiple partial match feature sets while tak-ing steric overlap into account. Moreover, by separating the problem into torsional andCartesian components, the program avoids the need to have template molecules.

11:25 High Strain Energies of Bound Ligands - What is Going on?Paul Labute, President, Chemical Computing Group

The prediction of the bioactive bound conformation of a candidate ligand is important forcomputational methodologies such as pharmacophore search and docking. The strain ener-gy of a conformation (relative to the global minimum energy) is often used as a criterionfor rejection of a conformation from consideration. Recent molecular mechanics studiesusing ligand-receptor complexes from the PDB have suggested that high strain energies (>10 kcal/mol) are not only possible but routinely observed. We present the results of com-putational experiments that attempt to explain these observtions and determine theirvalidity.

NEW TECHNOLOGIES & HOT TOPICS

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Hotel Information

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Flight Discounts

Seaport HotelOne Seaport LaneBoston, MA 02210 Phone: 617-385-4000 Fax: 617-385-4001Room Rate: $206 s/d Reservation Cutoff Date: May 23, 2006. Please call the hotel directly to makeyour room reservation. Identify yourself as a Cambridge Healthtech Institute con-ference attendee to receive the reduced room rate. Reservations made after thecut-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, soplease book early. For additional transportation information, parking garageoptions and driving directions to the Seaport Hotel please visit their website atwww.seaportboston.com.

Special discount rentals have been established with AVIS for this con-ference. Please call AVIS directly at 800-331-1600 and referenceyour Avis Worldwide Discount (AWD) Number J868190.

The MBTA’s Silver Line Waterfront provides service from the World TradeCenter (WTC) Station to Logan International Airport terminals every 10minutes during the weekday and every 15 minutes during the weekend.Additionally, bus routes 448, 449, and 459 provide service to LoganAirport from the World Trade Center Boston/Seaport District via the TedWilliams Tunnel/I-90 West. Please visit the MBTA website to learn moreabout schedule information.

Taxi service is provided just steps away at the Seaport Hotel.Additionally, water taxis are available from the Seaport WTC to theLogan Airport marine terminal where free ground transportation awaitsto all airport terminals. Rowes Wharf Water Taxi picks up at the MBTADock on the west side of the WTC by Dunkin Donuts (between the Spiritof Boston and Spirit Elite). City Water Taxi also provides water taxi serv-ice. The City Water Taxi dock is located at the east apron of WTC, nextto Sovereign Bank. In addition, BostonCoach offers sedan service toLogan International Airport.

Discounted fares are available on United, United Express, United code shareflights (UA*) operated by US Airways, and US Airways Express. You canreceive up to a 15% discount if you or your travel agent call United's toll-freenumber 1-800-521-4041 and refer to the Meeting ID Number 579YS.

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11:40 New Computational Methods for Structure-BasedDrug Design

Richard Friesner, Ph.D., Department of Chemistry, Columbia University

We have developed new technologies for significantly improving the prediction of bindingmodes and binding affinities of protein-ligand complexes. Incorporation of polarization ofthe charges on the ligand, via coupling of mixed quantum mechanics/molecular mechanicsmethods to docking, enable a dramatic improvement in the robustness of binding modeprediction. Protein structure prediction methods can be used to efficiently model inducedfit effects. Finally, a novel scoring function, based on hydrophobic enclosure of the ligandby protein residues, has been developed for assessing binding affinity. Recent results vali-dating this scoring function via explicit molecular dynamics simulations will be presented.Applications to a wide range of pharmaceutically interesting targets, such as CDK2 and p38map kinase, will be discussed.

12:10pm Luncheon Technology Workshop

Sponsored by

Focused Combinatorial Libraries via a NovelStructure-Based Design Methodology

Woody Sherman, Ph.D., Applications Scientist, Department of Applications,Schrödinger

Short Proposal: Combinatorial library design has been evolving toward greater use of smallfocused libraries that are biased toward a specific target or class of targets and exhibit opti-mal drug-like physiochemical properties. We will present the application of a novel com-putational method that performs rapid virtual screening of combinatorial libraries to elim-inate unpromising compounds before they are synthesized. This approach is based on newtechnology that dramatically reduces the combinitorial complexity of the search problemin order to generate an optimized focused library. Furthermore, the program allows for theinclusion of predicted ADMET properties into the overall library selection process. A num-ber of case studies using this methodology will be presented.

12:45 Last Chance to View Posters & Exhibits

1:25 Chairperson's Remarks

1:30 NMR-Based Discovery of Novel Protein-ProteinInteraction Modulators

Markus Schade, Ph.D., Vice President of NMR Drug Discovery, Combinature Biopharm AG

By using NMR-based fragment screening, we successfully identified novel, chemicallydiverse classes of fragment ligands for a demanding protein-protein-interaction (PPI) tar-get, namely the PDZ domain of human AF6. We derived a 3D pharmacophore modeldirectly from the NMR binding site information and utilized it for the first round of chem-ical optimization. For the highest affinity derivative, we determined the 3D protein-frag-ment complex structure by NMR and used it to guide the second round of fragment-to-leadoptimization. This case study demonstrates how NMR-derived structural information sup-ports fast and efficient fragment optimization chemistry.

2:00 Structure-Guided and Property-Guided Design inDrug DiscoveryKlaus Müller, Ph.D., Pharmaceutical Research-Head of Science &Technology Relations, F. Hoffmann-La Roche Ltd.

Local bulk increase is a recurrent stratagem in drug discovery. However, this is typicallyaccompanied by an undesired increase in lipophilicity. In our search for liponeutral’ bulkincrease, we identified a structural subunit that has been largely overlooked in medicinalchemistry. We find that this unit has the potential to modify compound properties inunique ways and may solve several problems commonly encountered in medicinal chem-istry

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2:30 How Much More Effective will Drug DiscoveryBecome in the Next 10 Years?

Most would agree that the process of discovering new medicines is highly chaoticbecause our knowledge — of chemistry, of biophysics, of biology, and of clinicalmedicine — is far too thin. But it is useful to consider what progress we mightexpect towards the “industrialization” of drug discovery in the coming decade.

Specific questions include: • How much progress should we expect — absolutely none, a great

deal, or something in between? • In which domains will progress be fastest? • What choices should we make today to enable the greatest degree of

progress? • Which target families and disease areas lend themselves to the

greatest opportunities for progress?This will be a no-holds-barred, forward-looking, provocative sessionwith plenty of audience participation. Be prepared to state — anddefend — your views!

Anchor: Mark Murcko, Ph.D., Vice President and ChiefTechnology Officer, Vertex Pharmaceuticals, Inc.

Provocateur: Sean Ekins, Ph.D., Vice President Computational Biology,ACT, LLC

Scholar: William L. Jorgensen, Ph.D., Whitehead Professor ofChemistry, Department of Chemistry, Yale University

Designer: Tomi K. Sawyer, Ph.D., Senior Vice President, DrugDiscovery, ARIAD Pharmaceuticals

Pioneer: Klaus Müller, Ph.D., Pharmaceutical Research - Science &Technology Relations Director, F. Hoffmann-La Roche Ltd.

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Please send information about related CHI conferences:

❒ Protein Kinase Targets (KIN)❒ World Pharmaceutical Congress (WPC)❒ Medicinal Chemistry (MCH)❒ Drug Discovery Chemistry (LDS)

YES! Register me for ❒ Structure-Based Drug Design 651 F

Registration Information❒ Mr. ❒ Ms. ❒ Mrs. ❒ Dr. ❒ Prof.

Name

Job Title Div./Dept.

Company

Address

City/State/Postal Code

Country

Telephone

Would you like to receive event updates via fax? ❒ Yes ❒ No Fax

Email**Email is not a mandatory field. However, by excluding your email you will not receive notification about online access to pre-con-ference presenter materials, conference updates and networking opportunities.

PRICING INFORMATION Commercial Academic, Government,Hospital-Affiliated

Pre-Conference Short Course: June 14Designing Structure-Based Kinase Inhibitors ❒ $595 ❒ $295Conference Only: June 15-16Early Registration Discount until March 24, 2006 ❒ $1045 ❒ $545 Advance Registration Discount until May 4, 2006 ❒ $1195 ❒ $620 Registrations after May 4, 2006, and on-site ❒ $1395 ❒ $695Conference & Short Course: June 14-16Early Registration Discount until March 24, 2006 ❒ $1245 ❒ $660 Advance Registration Discount until May 4, 2006 ❒ $1395 ❒ $735 Registrations after May 4, 2006, and on-site ❒ $1595 ❒ $810Additional Discounts:Poster Discount ❒ $50 off ❒ $50 offISCB Member Discount ❒ 10% off ❒ 10% offAlumni Discount (See page 5 for details) ❒ 25% off ❒ 25% off❒ I cannot attend but would like to purchase the conference CD for $250 (plus shipping).

Massachusetts delivery will include 5% sales tax.

❒ Please send information on exhibiting and opportunities to present workshops.

PAYMENT INFORMATION❒ Enclosed is a check or money order payable to Cambridge Healthtech Institute, drawn on a U.S. bank, in U.S. currency.❒ Invoice me, but reserve my space with credit card information listed below.

Invoices unpaid two weeks prior to conference will be billed to credit card at full registration rate. Invoices must bepaid in full and checks received by the deadline date to retain registration discount. If you plan to register on site,please check with CHI beforehand for space availability.

❒ Please charge: ❒ AMEX (15 digits) ❒ Visa (13-16 digits) ❒ MasterCard (16 digits) ❒ Diners Club (14 digits)

Card # Exp. Date

Cardholder

Signature

Cardholder’s Address (if different from above)

City/State/Postal Code

Country

PRESENT A POSTER AND SAVE $50

Cambridge Healthtech Institute encourages attendees togain further exposure by presenting their work in theposter sessions. To secure a poster board and inclusion inthe conference CD, your abstract must be submitted,accepted and registration paid in full by May 25, 2006Register online to use the Poster Abstract Submissionform or, if you register by phone, fax, or mail, you willreceive Poster Abstract Submission guidelines via email. I am interested in presenting a poster at:

❒❒ Structure-Based Drug Design and will submit a completed one-page abstract by

May 25, 2006 (Please Note: Registration must be paid in

full to present poster.)

Title

CHA ADVANCES LIFE SCIENCES REPORTS:Affiliate authors collaborate with CHA experts to pro-vide a series of reports that evaluate the salient trendsin pharmaceutical technology, business, and therapymarkets. For more information, visitwww.chadvisors.com, or contact Cindy Ohlman atcohlman@chadvisors.com or 781-547-0202.

ADDITIONAL REGISTRATION DETAILS

Each registration includes all conference sessions, postersand exhibits, food functions, and a copy of the conferenceCD.

GROUP DISCOUNTS

Special rates are available for multiple attendees fromthe same organization. Contact David Cunningham at 617-630-1372 to discuss your options and take advan-tage of the savings.

HANDICAPPED EQUAL ACCESS

In accordance with the ADA, Cambridge HealthtechInstitute is pleased to arrange special accommodations for attendees with special needs. All requests for suchassistance must be submitted in writing to CHI at least30 days prior to the start of the meeting.

SUBSTITUTION/CANCELLATION POLICY

In the event that you need to cancel a registration, you may:

• Transfer your registration to a colleague within yourorganization

• Credit your registration to another CambridgeHealthtech Institute program

• Request a refund minus a $100 processing fee per conference

• Request a refund minus the cost ($250) of orderinga copy of the CD

NOTE: Cancellations will only be accepted up to twoweeks prior to the conference.

Program and speakers are subject to change.

Register 3 — 4th is Free

Individuals must register for the same conference or conferencecombination and submit completed registration forms togetherfor discount to apply. Please reproduce this registration form asneeded.

TO REGISTER: Web: www.healthtech.com • Phone: 617-630-1300 or toll-free in the U.S. 888-999-6288 • Fax: 617-630-1325 • Mail: 1037 Chestnut Street, Newton Upper Falls, MA 02464 USA

Please refer to the Keycode below:

SSttrruuccttuurree--BBaasseedd DDrruugg DDeessiiggnn June 14-16, 2006 • World Trade Center • Boston, Massachusetts

BestValue