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CHI's 13th Annual Structure-Based Drug Design Conference - Day 3

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2013 Archived Content


7:30 am Breakfast Roundtable Discussions

These are moderated discussions with brainstorming and interactive problem solving, allowing conference participants from diverse backgrounds to exchange ideas, experiences, and develop future collaborations around a focused topic.

Table 1. Discovering Allosteric Binding Pockets• Motivation
• Discuss existing methodologies
• Exchange ideas, Propose future schemes
Moderator: Zoe Cournia, Ph.D., Investigator, Biomedical Research Foundation, Academy of Athens 

Table 2. The Role of Structure-Based Approaches in Understanding Polypharmacology• The many roles of structure-based approaches on polypharmacology
• How can we effectively compare binding sites?
• How can we optimize the use of fragment-based approaches to modulate the binding to several targets?
• Are free-energy methods ready to deal with selectivity issues?
Moderator: Hugo Gutierrez de Teran, Ph.D., Guest Researcher, Cell and Molecular Biology, Uppsala University 

Table 3: Drug Resistance

•  The special role that structure-based drug design can play in treating drug resistant infectious diseases
•  How considering the evolution of resistance during drug development could produce drugs with more long-lasting clinical efficacy
•  How drug resistance can be used as a tool to understand mechanism of drug action
Moderator: Adam C. Palmer, Ph.D., Postdoctoral Fellow, Department of Systems Biology, Harvard Medical School 



8:30 Chairperson’s Remarks

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

8:40 Case Histories of Recent Fragment-Based Drug Discovery Projects

Christopher MurrayChristopher W. Murray, Ph.D., Vice President, Discovery Technology, Astex Pharmaceuticals

Here we describe some case histories of applying fragment-based drug discovery to challenging drug targets. This will include the design of protein-protein interaction inhibitors of IAP family proteins and the design of allosteric inhibitors of full-length NS3 proteins from the Hepatitis C Virus. The presentation will discuss the difficulties associated with applying fragment-based drug discovery to challenging target classes and will discuss ways in which these can be mitigated.

9:10 Computational Protein Mapping to Drive the Development of Fragment Hits into Leads

Sandor Vajda, Ph.D., Professor of Biomedical Engineering and Chemistry, Director, Biomolecular Engineering Research Center, Boston University

Fragment-based drug design (FBDD) starts with finding fragment-sized compounds that are highly ligand efficient and can serve as a core moiety for developing high-affinity leads. Although the core-bound structure of a protein facilitates the construction of leads, effective design is far from straightforward. We show that protein mapping, a computational method developed to find binding hot spots, provides information that complements the fragment screening results and can drive the evolution of core fragments into larger leads with a minimal loss or, in some cases, even a gain in ligand efficiency.

9:40 Determination of Binding Poses, Kinetics and Energetics in Fragment-Based Design

Gianni De FabritiisGianni De Fabritiis, Ph.D., Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB)

Recently, we have been able to quantitatively reconstruct the complete binding process of several molecular systems in terms of binding poses, kinetics, affinities and pathways of binding. The key to reaching the timescales (microseconds and beyond) of these processes is high-throughput molecular dynamics, i.e. the capability to generate and then analyze thousands of MD short trajectories.  I will discuss the technology involved to reach these timescales and highlight the novel insights we have obtained regarding protein-ligand complexation.


10:10 Coffee Break in the Exhibit Hall with Poster Viewing

10:40 The Tip of the Iceberg and the Chemical Universe: Fuzzy Hit Finding Under Synthetic Feasibility Conditions

Carsten DeteringCarsten Detering, Ph.D., CEO, BioSolveIT, Inc.

We have come up with a method that addresses the problem of crowded patent space. It captures existing available chemistry in a company and thus allows the researcher to fuzzily search in a larger portion of the chemical universe available to him/her. Results are returned with their underlying chemical synthesis, which renders retro-synthesis unnecessary. Time saved can be invested in other Medicinal Chemistry efforts. The talk will highlight the method as well as several application examples.

Schrodinger11:10 Advances in Predicting Protein-Protein Binding Affinity and Protein Stability

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

The field of biologics continues to grow in importance in the pharmaceutical industry. To address the increasing need for computational tools to model biologics we have developed the Biologics Suite, which contains a broad range of task-driven applications tailored specifically to the field of biologics. Our objective was to blend an easy-to-use interface with state-of-the-art molecular simulations and de novo prediction, providing researchers with access to intuitive modules for protein-protein docking, estimation of residue mutation effects, disulfide stabilization, antibody modeling, determination of aggregation hotspots, and additional advanced simulations. Here, we present validation work on a sampling of the modules.


11:40 Q&A with Morning Speakers

12:10 Enjoy Lunch on Your Own


1:25 Chairperson’s Remarks

Dafydd Owen, Ph.D., Associate Research Fellow, Biotherapeutics Worldwide R&D, Pfizer Worldwide Medicinal Chemistry

1:30 How Does a Small-Molecule Inhibitor Bind at the Protein-Protein Interface of Interleukin 2?

Yibing ShanYibing Shan, Senior Scientist, DE Shaw Research

An increasingly important new frontier of drug discovery centered on using small-molecule inhibitors to selectively bind at the interfaces of specific protein-protein interactions (PPI) involved in disease development.  A great challenge in the design of PPI inhibitors, however, lies with the fact that the geometrical features of PPI binding sites are often invisible prior to the binding.  Thus understanding how a small molecule binds and how the binding site arrives at the bound conformations in this process is highly desirable.  To this end, we conducted unguided molecular dynamics to simulate the complete molecular process of a small molecule SP4206 binding to interleukine-2α (IL-2α) protein.  In two of these simulations, the small molecule correctly identified its target binding site, forming a complex virtually identical to the crystallographically determined bound structure.  The simulations provided an atomic-level view of the process by which a small molecule binds at the relatively flat protein-protein interface while the binding site adopts its bound conformation. These simulations indicated that the binding process of SP4206 is one of induced fit.  Similarly simulations of IL-2α interactions with chemical fragments including fragments of SP4206 further suggested that specific interaction of a chemical fragment and a protein requires a threshold molecular weight for the fragment.


2:00 From Determinants of RUNX1/ETO Tetramerization to Small-Molecule Protein-Protein Interaction Inhibitors Targeting Acute Myeloid Leukemia

Holger GohlkeHolger Gohlke, Ph. D., Professor, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Düsseldorf

A promising way to interfere with biological processes is through the control of protein-protein interactions by means of small molecules. Recent advances in the understanding of the energetics and dynamics of protein-binding interfaces open up a way to apply rational design approaches for finding protein-protein interaction modulators (PPIM). Here, we successfully identify small-molecule inhibitors of the dimer to tetramer transition of the NHR2 domain within the RUNX1/ETO fusion protein, a novel target for the treatment of acute myeloid leukemia.

2:30 Structure-Based Guided Development of Focused Chemical Library Dedicated to Orthosteric Modulation of Protein-Protein Interactions

Xavier MorelliXavier Morelli, Ph.D., Group Leader, Cancer Research Center of Marseille, CNRS

This talk will address some challenging issues: biological and chemical spaces of PPI with known orthosteric inhibitors, ligandability assessment of protein-protein interactions, design and validation of chemical libraries dedicated to PPIs.


3:00 Refreshment Break


3:15 Design and Develop Bromodomain Inhibitor for Cancer Therapy

Jun QiJun Qi, Ph.D., Senior Research Scientist, Medical Oncology, Dana-Farber Cancer Institute

In cancer, epigenetic proteins are promising and intensely studied targets for therapeutic drug discovery. Among the chromatin-modifying enzymes, so-called epigenetic “writers”, “readers” and “erasers”, chromatin-binding modules or epigenetic “readers” have received comparatively little attention perhaps owing to perceptions regarding the difficulty of targeting protein-protein interactions. Motivated by this challenge, we have developed first-in-class, drug-like inhibitors of “bromodomain and extraterminal domain” epigenetic readers (BETs) for mechanistic study and therapeutic application in cancer. We are continuously integrating the transcriptional consequences of BETi with changes in the epigenomic landscapes of cancer cells to elucidate the mechanisms underlying response to BETi using chemical and genetic perturbations.

3:45 The Impact of Structural Data on Epigenetic Probe Discovery for the Public Domain

Dafydd OwenDafydd Owen, Ph.D., Associate Research Fellow, Biotherapeutics Worldwide R&D, Pfizer Worldwide Medicinal Chemistry

Research into the role of epigenetics in disease could be significantly accelerated if cell-active chemical probes for such targets were available to the research community, through a collaborative, open-innovation model. Pfizer is a member of a public-private partnership led by the Structural Genomics Consortium (SGC) to help identify a suite of high-quality chemical probes for epigenetic targets. This partnership is unique in that it brings the medicinal chemistry expertise within industry together with biological expertise in academia to drive basic research in an emerging area of important biology of potential relevance to many diseases. The impact of structural biology on probe discovery will be presented.

4:15 Closing Remarks

4:30 End of Conference

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