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Sponsoring Publications:
CHI's Life Sciences Informatics: From Data to Drugs
Drug Discovery and Development
Current Drug Discovery
Journal of Computer Added Molecular Design
CHI's Advances in Lead Optimization
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Dr. Philip Dean, De Novo Pharmaceuticals Ltd.
Dr. Leo Grinius, Procter & Gamble Pharmaceuticals
Dr. Thomas L. James, University of California, San Francisco
Dr. Christian Lemmen, BioSolveIT GmbH
Dr. Christopher Lepre, Vertex Pharmaceuticals Incorporated
Dr. Paul Lyne, AstraZeneca
Dr. Tomi Sawyer, Ariad Pharmaceuticals, Inc.
Dr. Brian Shoichet, Northwestern University

This past year has seen a steady and exciting growth of novel inhibitors identified through computational analysis of target structure. A combination of more structures, advances in homology modeling, better docking and scoring tools, fragment-based methods, and advances in virtual screening has been fundamental in this progress. De novo design of small molecules is clearly becoming a valuable and integral part of the drug discovery, and the results are emerging. Join us to also hear several case studies of successful generation of leads from structure-based design and medicinal chemistry efforts and learn how to apply these approaches to make your own discovery and development more efficient and productive.
Backbone trace of the homodimer HIV-Protease (blue) together with a known inhibitor (white). 
Courtesy of Prof. Matthias Rarey, ZBH, University of Hamburg. Graphic created with FlexV™ of BioSolveIT GmbH


7:30-8:30am Registration and Continental Breakfast



8:30-8:40 Chairperson's Opening Remarks
Dr. Christian Lemmen, BioSolveIT GmbH

Virtual High-Throughput Screening: New Developments
Dr. Thomas Lengauer, Director of the Institute for Algorithms and Scientific Computing, Max-Planck Institute for Informatics
New developments in the field of virtual high-throughput screening will be summarized. Our target scenario is the screening of hundreds of thousands or millions of compounds in drug databases and up to billions of potential compounds that can be assembled from combinatorial or fragment spaces.

9:25-9:55 Virtual Screening Using a High-Throughput Docking System
Dr. Robert Klein, Head of Scientific Computing Frankfurt, Bayer CropScience GmbH
So-called Linux clusters based on standard PC technology provide considerable computing performance at moderate costs. Together with fast docking algorithms in parallel mode, hundreds of thousands of molecules can thus be docked per week or even per day. Strengths and weaknesses of the virtual screening techniques are discussed.

9:55-10:25 Structure-Based Virtual Screening: Strategies and Tricks
Dr. John W. Liebeschuetz, Group Leader, Molecular Modelling, Tularik Ltd.
Structure-based virtual screening and library design are rapidly becoming mainstream methodologies for lead discovery and optimization. However, there are many different ways in which virtual screening can be carried out. Here we present some strategies and some ideas for practical virtual screening that have proved of benefit to in-house programs.

10:25-10:55 Refreshments and Poster Viewing in the Exhibit Hall



10:55-11:25 Discovery of a Nanomolar Kinase Inhibitor by High-Throughput Docking
Dr. Eric Vangrevelinghe, Labhead, Molecular and Library Informatics, Novartis Pharma AG

11:25-11:55 The Effect of Different Virtual Screening Protocols on Hit Enrichment for Cyclin-Dependent Kinase 2
Dr. Judith Guenther, Schering AG
The cyclin-dependent kinase 2 (CDK2) is one of the most important targets in current cancer research. A number of CDK2 protein-inhibitor complexes are available in the PDB, revealing considerable protein flexibility within the ligand-binding pocket. We have applied different virtual screening protocols, including standard sequential FlexX docking in different CDK2 X-ray structures, docking with pharmacophore constraints using FlexX-Pharm, and docking into an ensemble of ligand-binding pockets using the FlexE module. We will describe the results in terms of hit enrichments for a data set comprising known CDK2 inhibitors from the literature and compounds without any reported kinase activity from the world drug index.

12:00-1:30 Lunch on your own or technology workshop (sponsorship available)

1:30-1:40 Chairperson's Remarks
Dr. David Hartsough, Director, Information Technologies, ArQule

1:40-2:10 Identification of Potent VLA4 Inhibitors Using Virtual Screening
Dr. Juswinder Singh, Associate Director, Structural Informatics, Biogen
We have discovered potent inhibitors of VLA4 using virtual screening based upon the X-ray structure of the ligand, VCAM-1. We compare the virtual screening results with those from traditional medchem. Finally, we demonstrate the utility of our compounds in animal models of asthma.

2:10-2:40 Quasi2™ vHTS Identification of Small Molecule Inhibitors of Beta Secretase
Dr. David Manallack, Head of Applied Design, De Novo Pharmaceuticals Ltd.
The enzyme Beta-secretase (BACE) is believed to play a pivitol role in plaque formation during the progression of Alzheimer's disease. Inhibition of BACE has become a key strategy in the race to develop therapeutic agents for this debilitating condition. Given the nature of the BACE active site, numerous peptidic inhibitor series have emerged from pharmaceutical research programs that, while potent, are unlikely to result in marketable drugs. Using proprietary virtual high-throughput screening (vHTS) technology, Quasi2™, on available structural information, De Novo Pharmaceuticals has succeeded in identifying nonpeptide lead scaffolds with demonstrated low micromolar potency. This presentation will detail our technologies and their application in De Novo's BACE discovery program.



2:40-3:10 Three-Dimensional Structures and Function of G-Protein Coupled Receptors
Dr. William A. Goddard, III, Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics Director, Materials and Process Simulation Center (MSC), California Institute of Technology
We have developed first-principle methods (MembStruk) to predict the three-dimensional structures of G-protein coupled receptors (GPCRs). These receptors play a critical role in cell communications and in sensing the outside world (vision, smell, taste, and pain). With the single exception of bovine rhodopsin, there are no experimental 3-D structures available for GPCRs despite their importance to pharma. Thus, to validate our predicted structures we developed new techniques (HierDock) to predict the binding site and binding energies of various ligands. These results can then be compared to the results of mutation experiments. We also use these 3-D structures to predict the binding of other agonists and antagonists and compare the results to available experiments. The results have been excellent, and we are now designing new more selective ligands that can be tested experimentally. We will discuss results for several systems selected from adrenergic receptors (which bind epinephrine, norepinephrine, beta-blockers), dopamine receptors, olfactory receptors, serotonin receptors, pain receptors, histamine receptors, and taste receptors.

3:10-3:40 Refreshments and Poster Viewing in the Exhibit Hall

3:40-4:10 Novel p38 MAP Kinase Inhibitors
Dr. Suresh B. Singh, Merck Research Laboratories
A new generation of p38 inhibitors based upon the literature was developed into potent, selective, and orally bioavailable compounds. This new series of compounds bind to p38a in a unique fashion not observed in any other kinase:inhibitor complex. The unique binding mode of this novel series of compounds is believed to be responsible for their selectivity towards p38.

4:10-4:40 Guided Docking: Incorporating Ligand-Based Information into Receptor-Based Methods
Dr. Jordi Mestres, Computational Medicinal Chemistry, Organon Laboratories Ltd.
The basic idea is to incorporate in the docking procedure structural information about known ligand binding modes and/or pharmacophoric features derived from ligand-bound protein structures and/or pharmacophore models. The resulting methods exploit maximally the structural information available from both receptor and ligands. Applications to assessing the binding mode and virtual screening of noncovalent and covalently bound ligands of serine proteases will be presented.

4:40-5:10 A Novel Proteomic Approach Simultaneously Identifies Drug Targets and Lead Compounds for Cell Signaling Pathways in Cancer Dr. Michael Yaffe, Assistant Professor, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology
Identification of novel drug targets involved in cell cycle control is a major rate-limiting step in anticancer drug development efforts. I will describe a novel pep-tide vs. protein library screening approach that simultaneously (1) reveals novel phospho(Ser/Thr)-binding modules involved in mitotic control, (2) provides lead compounds for structure-based drug design and high-throughput screening, and (3) provides sequence information for bioinformatics-based decoding of signal-ing pathways disrupted in cancer. to carry out directed searches for novel medicinal chemistry leads. This presentation describes the successful application of the SHAPES strategy (a lig-and- based method for NMR screening of small, druglike molecules) and SBDD to discover and optimize leads for a variety of targets, including kinases (e.g., Jnk3) and the fatty acid binding protein ALBP.

5:10-6:10 Networking Reception in the Exhibit Hall                     Sponsored by:



7:30-8:15am Technology Breakfast Workshop

Workshop Sponsors:

Leveraging the Chemistry Knowledge in Your Company: Archiving Reactions, Enumerating and Prioritizing Libraries, Optimizing Leads.
Presented by: Dr. Kristina Kurz, Associate Director Business Development



8:30-8:40 Chairperson's Remarks
Dr. Tom Sawyer, Ariad Pharmaceuticals, Inc.

8:40-9:10 Docking and De Novo Design: How Good Are Our Predictions?
Dr. Martin Stahl, Head of Molecular Design, F. Hoffmann-La Roche Ltd.
This talk will address key issues of two complementary techniques in structure-based design. Pros and cons of some current docking tools will be outlined; the inclusion of pharmacophore constraints in docking calculations will be discussed. Recent developments in de novo design will be presented.

9:10-9:40 SAR by X-Ray: Application of Fragment-Based Screening to the Design of Nanomolar Inhibitors of Src SH2
Dr. Ram Dharanipragada, Principal Scientist, Highthroughput Medicinal Chemistry, Drug innovation & Approval, Aventis Pharmaceuticals
Biophysical methods, such as NMR and X-ray crystallography, are becoming increasingly popular early in lead generation, owing to their effectiveness in identifying low-affinity, low-molecular-mass "fragments" and aiding their development into potent compounds. Lesuisse et al. now highlight the potential of such approaches by using X-ray-based screening of molecular fragments to develop nanomolar inhibitors of the SH2 domain of Src, a kinase involved in bone resorption that represents a potential target for the treatment of osteoporosis.

9:40-10:10 Combination of NMR Screening with Structure-Based Drug Discovery
Dr. Christopher Lepre, Principal Investigator, Structural Biology, Vertex Pharmaceuticals Incorporated
NMR screening has been combined with a variety of complementary methods-such as virtual screening, HTS, combinatorial chemistry, and X-ray crystallography-to carry out directed searches for novel medicinal chemistry leads. This presentation describes the successful application of the SHAPES strategy (a ligand-based method for NMR screening of small, druglike molecules) and SBDD to discover and optimize leads for a variety of targets, including kinases (e.g., Jnk3) and the fatty acid binding protein ALBP.

10:10-10:40 Refreshments and Poster Viewing in the Exhibit Hall

10:40-11:10 Challenges and Pitfalls of Predicting Protein-Ligand Interactions: PTP-1B Case Study
Dr. James Rizzi, Director, Computational Technology, Array BioPharma Inc.
This talk focuses on the challenges of using X-ray structures to guide medicinal chemistry efforts. Issues surrounding the protein, structural water interactions, and ligand perturbations are explored using PTP-1B as the case study. Fragment-based methods versus whole molecule docking approaches are compared. The ability to rank the best possible inhibitors and the implications for doing virtual screening are addressed along with a novel scoring algorithm to address some of the shortcomings with current methods.

11:10-11:40 Modeling Protein Flexibility by Dimensionality Reduction
Dr. Miguel Teodoro, Rice University
Flexibility plays a critical role in protein function and as a result many proteins cannot be successfully described by a rigid structure for drug design applications. Modeling protein motions, such as the induced fit effect, constitutes a computationally hard problem due to the high dimensionality of the conformational search space. In this talk, we present a method to efficiently incorporate protein motion in structure-based drug design.

11:40-12:10 Structure-Based Screening and Design in Drug Discovery
Dr. Mats Wikström, Associate Professor and Chairman of the Target Review Committee, Biovitrum
Structure-based screening combines the power of NMR spectroscopy, automatic docking, and X-ray crystallography and provides the means to apply structural information (NMR, modeling, and X-ray) early in the projects to identify hits, select targets, and optimize the hits in terms of their affinities and specificities. Some recently developed novel screening techniques to perform site-specific screening will be discussed with the emphasis on the development of new drugs for the treatment of diabetes and obesity.

12:10-1:10 Luncheon 

1:10-1:30 Dessert and Poster Viewing in the Exhibit Hall



1:30-1:40 Chairperson's Remarks
Dr. Paul Lyne, Principal Scientist, AstraZeneca

1:40-2:10 Design of a Second-Generation HIV Protease Inhibitor-Lopinavir
Dr. Hing L. Sham, Director, R4MA, Abbott Laboratories
Lopinavir is a second-generation protease inhibitor discovered via structure-based drug design. It is the antiviral component of KaletraTM, which has become the #1 protease inhibitor prescribed worldwide. The design and properties of lopinavir will be discussed.

Feature Case 

2:10-2:40 Analysis of the Basis of Specificity and Selectivity in Cyclin-Dependent Kinase Inhibition
Dr. Martin Noble, University Lecturer, Laboratory of Molecular Physics, University of Oxford
Key cellular processes that determine cell fate are regulated by the activity of cyclin-dependent kinases (CDKs), a fact that has implicated CDKs as potential targets in antiproliferative therapy. We have employed structure-based drug design to produce potent and specific inhibitors of CDK1/CDK2 that show promising activity against tumor-derived cell lines in vitro. We are now analyzing the atomic basis for CDK inhibitor specificity in order to transfer the lessons learned from CDK1/2 inhibition to inhibition of other members of the CDK family such as PfPK5 from Plasmodium falciparum, the causative agent of the lethal form of human malaria.

2:40-3:10 Scaffold-Based Drug Discovery across Protein Families
Dr. Dean R. Artis, Senior Director, Informatics, Plexxikon
Plexxikon is a drug discovery company that has developed an industrial-scale platform to generate novel, higher quality drugs more efficiently. Potent and selective drug leads are synthesized rapidly from chemically tractable and broadly acting scaffolds discovered by Plexxikon. Using uniquely integrated structure-based systems, the company has already discovered numerous novel chemical scaffolds for a number of therapeutically important protein families and representing hundreds of targets.

3:10-3:30Refreshment Break

3:30-4:00 Structure-Based Design of Novel Anti-infectives Targeted against the 50S Ribsomal Subunit
Dr. Zoltan Kanyo, Research Scientist, Structure-Based Drug Design, Rib-X Pharmaceuticals
Rib-X employs a directed approach to the discovery of novel anti-infective compounds targeting the 50S subunit of the ribosome. We leverage our medicinal chemistry resource by providing crystallographically derived structural data on our compounds bound to the 50S ribosomal subunit. This ability, coupled with talented computational and biological assay teams, allows the rapid compression of the drug discovery cycle.

4:00-4:30 Panel Discussion

4:30-5:00 Close of Conference


De Novo Pharmaceuticals is a privately held integrated lead discovery company based in Cambridge, UK. We are one of Europe's largest centres for computational drug design with proprietary expertise in de novo and screening technologies. We leverage these technologies together with chemistry and screening platforms to rapidly create and reduce to practice novel, patentable molecules as candidates for drug development.


ArQule designs Optimal Chemical Entities™ (OCEs) using a multidisciplinary approach that integrates intelligent molecule design and high-throughput, automated chemistry, in parallel, with experimental and predictive modeling of ADMET parameters. These OCEs are target-relevant small molecules whose druglike characteristics have been optimized prior to their entry into preclinical studies. ArQule engages in both partnered and wholly owned drug discovery programs resulting in shared and exclusive commercial rights

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