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Structure-Based Drug Design - Day 1

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Wednesday, June 23, 2010

7:45 am Workshop Registration & Morning Coffee

8:25 Organizer’s Welcoming Remarks

Micah Lieberman, Executive Director, Conferences, Cambridge Healthtech Institute



Therapeutic Target Space:
Methods for Druggability Assessment

8:35 Workshop Chairperson’s Remarks

Tomi Sawyer Ph.D.Tomi Sawyer, Ph.D., Chief Scientific Officer, AILERON Therapeutics; Editor-in-Chief, Chemical Biology & Drug Design






8:45 Assessing Druggability for Protein-Protein Complexes: The 2P2I Database

Xavier Morelli Ph.D.Xavier Morelli, Ph.D., Group Leader, Drug Design, CNRS/ IMR Laboratory

Our group has developed innovating protocols targeting PPI inhibitions, such as the 2P2I approach (Betzi et al., PNAS 2007). However, the main actual impediment in further PPI inhibitors development relates on i) the absence of dedicated chemical databases and ii) the identification of druggable/targetable complexes. This conference will present: 1) A general introduction focusing on the biophysical parameters related to PPI’s 2) Our dedicated protein-protein database, 2P2IDB 3) Original Druggability parameters that could permit to differentiate druggable from non-druggable complexes.

9:15 Combining Small Molecule and RNAi Screens for Target Prioritization

Rajarshi GuhaRajarshi Guha, Ph.D., Research Scientist, Informatics, NIH Chemical Genomics Center

The talk will highlight how one might use high-throughput RNAi screens in combination with small molecule screens for target prioritization. Key to the approach is the network analysis of pathways that selected genes (from the RNAi screen) are embedded in, coupled with knowledge of small molecules involved in those pathways. In parallel we also consider the case where multiple targets maybe identified for a given small molecule and strategies that may be employed to quantify the relevance of each such target to the ligand in question. The presentation will highlight how one can make use of HTS data, integrating small molecule and RNAi experiments for the purpose of target prioritization. The audience will learn about new developments in network based approaches to analysis data from RNAi screens and approaches to merging such data with small molecule screening data.

9:45 Networking Coffee Break

10:00 Using Fragments to Assess Target Druggability

Rod Hubbard Ph.D.Roderick Hubbard, Ph.D., Professor and Senior Fellow, Structural Sciences, University of York and Vernalis

We have used experimental fragment screening against a range of targets (from kinases to protein-protein interaction targets). The hit rate does not always correlate with computational assessment of druggability, but can indicate where there are other issues with finding robust lead compounds against a Target. The experimental screen can be contrasted with computational assessment of structure through fragment docking approaches. This presentation will include further analyses of how target druggability can be assessed and comparison of experimental and computational approaches. The audience will gain a fuller understanding of the relationship between target structure, fragment screening hit rates and target druggability.

10:30 Identifying and Characterizing Binding Sites and Assessing Druggability

Woody Sherman Ph.D.Woody Sherman, Ph.D., Vice President, Applications Science, Schrodinger, Inc.

Identification and characterization of binding sites is key in the process of structure-based drug design. We present a method for identifying and analyzing binding sites, which can also be used to predict target druggability. In a large-scale validation, we correctly identify the known binding site as the top-ranked site in 86% of the cases, with best results (>98%) coming for sites that bind ligands with subnanomolar affinity. In addition, a modified version of the score employed for binding-site identification allows for the accurate classification of the druggability of proteins as measured by their ability to bind passively absorbed small molecules tightly.

10:00 Main Conference Registration



Selectivity Optimization:
Using Structure to Optimize Selectivity

11:00 Organizer’s Welcome & Chairperson’s Remarks

Micah Lieberman, Executive Director, Conferences, Cambridge Healthtech Institute

Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group (CCG)

11:15 Keynote Presentation

Structure-Based Design of AP24534, a pan-BCR-ABL Inhibitor Overriding the T315I Gatekeeper Mutation

David DalagarnoDavid Dalgarno, Ph.D., Vice President, Research Technologies, ARIAD Pharmaceuticals, Inc.

Resistance to BCR-ABL kinase inhibitors, such as imatinib, in patients with chronic myeloid leukemia (CML) is associated with the appearance of BCR-ABL point mutations that prevent effective drug binding, most notably to the T315 gatekeeper mutant. Using a structure-based approach we discovered the multi-targeted pan-ABL inhibitor AP24534, which inhibited T315I and all tested BCR-ABL mutants in biochemical and cellular assays, and completely abolished resistance in cell-based mutagenesis screens. Here we describe the optimization process leading to the discovery of AP24534, illustrated via X-ray co-structures, and compare the resistance profile of AP24534 to other BCR-ABL inhibitors. 

11:45 Special Co-Presentation

Achieving Remarkable Potency and Selectivity Against HCV Protease by Irreversible Covalent Inhibition Using Structure-Based Drug Design

Deqiang NiuDeqiang Niu, Ph.D., Principal Scientist/Project Leader, Medicinal Chemistry, Avila Therapeutics







Juswinder SinghJuswinder Singh, Ph.D., Co-Founder/Chief Scientific Officer, Avila Therapeutics

Using structure-based drug design, we identified a class of small molecules that irreversibly bond to a non-catalytic amino acid residue, cysteine 159, in NS3 protease. This approach significantly improved inhibitor potency against the viral proteases and also achieved exceptional selectivity due to the lack of structural homology between viral and host proteases. More importantly, the covalent inhibitor showed prolonged duration of action (>24 hours) after brief exposure of the replicon cells to the compound.

12:15 pm Embedding High-Throughput Structural Screening and Computational Bioactivity Prediction in Target Validation and Drug Discovery

Rick ArtisD. R. Artis, Ph.D., Senior Vice President, Global Research, Elan Pharmaceuticals, Inc.

Successfully integrating structural screening approaches early in the drug discovery process has shown promise in decreasing program time-to-entry into clinical development. However, while many of these efforts have been focused on fairly mature areas of biology, strategic use of these techniques can also accelerate the early stage in vivo proof of concept studies and help derisk potential new therapeutic avenues. Some success stories and results from our current technological approaches will be discussed. 

12:45 Luncheon Presentation (Sponsorship Opportunity) or Lunch on your Own

(Contact Katelin Fitzgerald at or 781.972.5458)


Protein-Protein Interaction
Targeted Drug Discovery

2:10 Chairperson’s Remarks

Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group (CCG)

2:15 Using Semi-Rational Design and Protein Folding to Engineer Highly Specific Protein-Protein Interactions for Therapeutic Intervention

Jody MasonJody Mason, Ph.D., Lecturer, Biological Sciences, University of Essex

Disrupting protein-protein interactions that are implicated in pathogenic events has the potential to cure countless deadly diseases. We are screening short peptide libraries using an assay we have developed to generate highly specific antagonists that bind and sequester key targets. Our initial sequences will establish rules for de novo design of stable and specific peptide-based drugs. A variety of in vitro (including steady state and kinetic methods) and in vivo techniques are used to characterise the peptides for efficacy.

2:45 Stapled α-Helical Peptides: The Twists and Turns of Drug Discovery

Tomi Sawyer Ph.D.Tomi Sawyer, Ph.D., Chief Scientific Officer, AILERON Therapeutics; Editor-in-Chief, Chemical Biology & Drug Design

The significant opportunity to expand drug discovery has been realized with respect to a plethora of protein-protein interactions that modulate biological pathways in varying diseases. In particular, many of such protein-protein interactions involve α-helical molecular recognition (e.g., BH3, p53 and Notch). We have developed a series of promising synthetic α-helical peptides that are stabilized by macrocyclic hydrocarbon bridges to advance ‘stapled’ peptides which possess quite profound in vitro and in vivo properties. This presentation will highlight progress in this fast emerging area of novel drug discovery and innovative technologies.

3:15 Networking Refreshment Break, Poster and Exhibit Viewing

4:00-5:00 Interactive Break-Out Discussion Groups

Concurrent break-out discussion groups are interactive, guided discussions hosted by a facilitator or set of co-facilitators to discuss some of the more poignant questions facing the industry. Delegates will join a table of interest to them and become an active part of the discussion at hand. It is an informal yet informative format that allows attendees to learn from each other and make some new contacts. To get the most out of this interactive format please come prepared to: share examples from your work, vet some ideas with your peers, be a part of group interrogation and problem solving, and, most importantly, participate in active idea sharing. 

TABLE 1: Integration of 3-D and 2-D structural information, for instance the ones from the PDB with those from PubChem

Host: Talapady Bhat, Ph.D., Project Leader, Biochemical Science, NIST

Discussion Points:
• The need (if any) for the Integration of 2-D and 3-D small molecule structural data
• What are current approaches and break through technologies and what are their limitations
• Semantic Web Concepts and rule-based structural ontologies for the integration of 2-D and
3-D structural data

TABLE 2: Use of Structure-Based Drug Design to Address Drug Resistance

Hosts: Juswinder Singh, Ph.D., Founder and CSO, Avila Therapeutics, Inc.
David Dalgarno, Ph.D., Vice President, Research Technologies, ARIAD Pharmaceuticals, Inc.

Discussion Points:
• How useful is SBDD in addressing drug resistance mutations
• What are the strengths and weaknesses of the current computational approaches
• Do we see any breakthrough technologies emerging in the near-term

TABLE 3: Computational Directions for Structure-Based Lead Optimization

Host: W. Patrick Walters, Ph.D., Senior Research Fellow, Group Head, Computational Drug Discovery Technologies, Vertex Pharmaceuticals, Inc.

Discussion Points:
• What constitutes a reliable validation of structure-based lead optimization tools, do real validations exist in the literature?
• Is docking and scoring a viable solution for lead optimization, how well do empirical scoring functions predict binding affinity?
• Can we use intermediate computational techniques such as MMPBSA/MMGBSA to drive a lead optimization program?
• Are more rigorous techniques such as FEP “ready for prime time”, where do improvements need to be made?

TABLE 4: Do We Get the Most Out of the Structural information in the PDB? Tips and Lessons Learned

Host: José Duca, Ph.D., Senior Principal Scientist, 3D - Drug Design Department, Merck Research Laboratories

TABLE 5: Why Aren’t We Designing the Perfect Drug as Soon as We Have a Crystal Structure?

Hosts: Rama Kondru, Ph.D., Principal Research Scientist, Hoffmann-La Roche
Ms. Elizabeth Sourial, Director, Scientific Services, Chemical Computing Group Inc.

Discussion Points:
• What are the current limitations of structure based design?
• How do we handle protein flexibility?
• What are the key protein-ligand interactions that we do not understand – like long range electrostatics?
• What are the new methods that can change the landscape in the future, if any?

TABLE 6: The Role of Structural Waters in Drug Design

Host: Woody Sherman, Ph.D., Vice President, Applications Science, Schrodinger, Inc.

Discussion Points:
• When is it best to bridge versus displace a water molecule?
• Should certain structural water molecules be avoided?
• Can activity cliffs be explained by waters?

TABLE 7: Matching SBDD Approaches with Targets: Do We Know How to Optimize Our Protocols?

Host: Sid Topiol, Ph.D., Head of US Computational Chemistry and Structural Investigations, Lundbeck Research, USA

Discussion Points:
• With numerous computational options (e.g., protein and/or ligand flexibility, homology modeling, energetic approximations, solvation effects) and target considerations
(e.g., X-ray resolution, multiple states), are we equipped to identify the best protocols?
• What role, if any, should be played by ligand-based methods in conjunction with SBDD?
• Experimental insights from protein/ligand interactions; are ligand methods (MedChem) or protein methods (X-ray, mutation) more informative?

TABLE 8:The Issue of Protein Flexibility in the Structure-Based Drug Design

Host: Jie Zheng, Ph.D., Associate Member, Department of Structural Biology, St. Jude Children’s Research Hospital

TABLE 9: Getting Around Scoring

Hosts: Matthias Rarey, Ph.D., Professor & Managing Director, ZBH Center for Bioinformatics, University of Hamburg
Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group (CCG)

Discussion Points:
The development of accurate protein-ligand scoring functions is the bottleneck for structure-based drug design over the past 20 years. In contrast of thinking how to improve
existing methods by another few percent, the focus of the discussion should be how to circumvent this difficult question:
• Are target-based scoring methods a solution?
• Can we develop classification schemes (binder - non binder), even if we are not able to make a good energy estimate?
• Is ranking simpler than scoring and if yes, can we make use of this? 

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5:00 - 6:00 Networking Reception in the Exhibit Hall


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