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Day 1 - Fragment-Based Drug Discovery


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7:15 am Registration and Morning Coffee




8:05 Chairperson’s Remarks
Roderick Hubbard, Ph.D., Senior Fellow, Research, Vernalis (R&D) Ltd.

8:15  Fragment-Based Lead Generation at AstraZeneca: Philosophy, Strategy and Some Case Stu-dies
Alex Breeze, Ph.D., Principal Scientist, Global Structural Chemistry, AstraZeneca
Fragment-based lead generation (FBLG) has recently emerged as an alternative to traditional high throughput screening (HTS) to identify initial chemistry starting points for drug discovery programs. This talk will describe experiences using FBLG at AstraZeneca. Topics covered will include screening library design, hit detection, evalu-ation of hit quality, and approaches to evolve fragments towards drug-like leads. Our use of FBLG will be exem-plified with some case studies from varied classes of therapeutic target.

8:45 Structure-Based Drug Discovery - From Fragment to Clinical Candidate 
Andrew J. Woodhead, Ph.D., Senior Chemist, Chemistry, Astex Therapeutics Ltd.
This presentation will outline Astex’s structure-based approach to drug discovery, from initial fragment hit identi-fication, through hit validation and then into lead optimization. Examples will be given detailing the discovery of low nanomolar lead compounds for the oncology targets CDK1/2 and Hsp90, with emphasis on the development of these into clinical candidates.

9:15  Experiences in Fragment-Based Discovery
Roderick Hubbard, Ph.D., Senior Fellow, Research, Vernalis (R&D) Ltd.
Over the past six years, we have developed, refined and applied fragment-based methods in a number of struc-ture-based discovery projects. In this presentation, I will review our experiences and some of the phenomena observed. As well as successful lead generation in various projects, I will also discuss similarities and differences in fragment binding to members of the same target family, conformational changes induced by fragments and comparison of different methods for identifying fragment binding. From these experiences, I will review what we believe are the next steps for developing and applying the methods. These include improved characterization of library content, design of novel fragments, decision support for fragment evolution and targeting protein-protein interactions.

9:45  Networking Coffee Break




10:15 Using Pharmacophore Queries and Electrostatic Maps to Retrieve Fragment Linker Groups and Scaffold Replacements in Drug Discovery
Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group Inc.
The use of pharmacophore queries to search virtual databases for novel fragment linker groups is presented. Ad-ditional pharmacophore features, determined either from known interactions or postulated from electrostatic mapping of the protein pocket are used to augment the query to preserve key interactions. Volume constraints are used to satisfy shape requirements. This paper presents a methodology for using standard pharmacophore features, projected special pharmacophore features and electrostatic mapping of the protein pockets for identify-ing fragment hot-spots in a receptor pocket and for linking fragments into a putative drug compound.  A few case studies are discussed to demonstrate the utility of the method.

10:45 NMR Spectroscopy in Hit Identification and Optimization Process and Reverse Chemical Ge-netics
Maurizio Pellecchia, Ph.D., Professor , IIDC and CC, Burnham Institute for Medical Research
Recently we reported on an NMR-based approach, named SAR by ILOEs (structure activity relationships by interli-gand nuclear Overhauser effect), that makes use of protein mediated ligand-ligand NOEs (ILOEs) in complex mix-tures to identify initial weak hits that are converted by synthetic chemistry approaches into bi-dentate compounds with higher affinity. In addition, we also reported on combining this approach with pharmacophore-based searches of possible linked molecules from large databases of commercially available compounds (Pharmacophore by ILOEs). Combined with functional studies using the resulting ligands, these methods represent ideal approaches to hit identification and to reverse chemical-genetics studies. Reverse chemical-genetics entails selecting a protein of interest, screening for a ligand for the protein, and finally determine the eventual phenotypic alterations that the ligand induces in a cellular context. Likewise, these methods enable the identification of protein’s hot spots by using small molecules, regardless of the knowledge of the function of the protein, and the development of a specific assay. Subsequently, such small organic molecules can be used in cellular assays to investigate the possible role of the target. In particular, the approaches were applied to the identification of the first inhibitor of the pro-apoptotic protein Bid and to find highly selective protein kinase inhibitors. We also will report on the use of paramagnetic probes for the design of potent and selective bi-dentate compounds against kinases and phosphatases.

11:15 NMR Techniques in Fragment-based Drug Discovery: Fragment SAR 
Edward R. Zartler, Ph.D., Research Fellow, BioProcess & Bioanalytical Research, Merck & Co., Inc.
Fragment-based Drug Discovery (FBDD) is a burgeoning technique in Drug Discovery.  An essential component to this technique is the use of biophysical tools as both primary and secondary screens.  NMR is widely regarded as the most versatile and utile of all the biophysical techniques.  This talk will focus on real-world application of NMR in the FBDD process, from hit generation to lead optimization.  The potential of using fragments to develop SAR, in the absence of chemistry, will also be discussed.

11:45  Pharmacophore Guided Fragment-Based Drug Design
Shikha O'Brien, Ph.D., Accelrys
Pharmacophores describing interactions between biological targets and ligands are an established screening tool at early stages of drug discovery. The use of fragment-based approaches in drug discovery has gained wide pop-ularity in recent years. We have recently introduced an in silico method that utilizes pharmacophores for a com-binatorial fragment-based approach applicable to the design of novel compounds, and for lead optimization. Starting with a pharmacophore (no requirement for protein structure) small molecular fragments can be rapidly assembled into new molecules.  Advantages of starting from fragments include an increased diversity in chemical space, but also the flexibility to incorporate drug-like properties at early stages of the design.

12:00 pm Luncheon Technology Workshop 
SPR Analysis in Fragment-Based Lead Generation
Annika Remaeus, M. Sc., Systems, R&D, GE Healthcare
Biacore™ A100 supports drug discovery from fragment screening to detailed characterization of leads. This workshop will demonstrate how label-free binding analysis offers efficient means to evolve fragments towards drug-like leads, with low target consumption. Topics covered will include removal of promiscuous compounds, screening for selective, active site-specific binders, ranking based on affinity, and lead evolution based on kinetic parameters.

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1:00 Break

1:25 Chairperson’s Remarks

1:30 The EVOlution™ platform for Fragment Based Drug Discovery
John Barker, Ph.D., Group Leader XrayCrystallography, Evotec AG
Evotec have assembled a FBDD platform centred around two complementary and highly sensitive detection techniques, fluorescence correlation spectroscopy and nuclear magnetic resonance, in addition to a newly designed collection of 20,000 diverse fragments. In our presentation we will discuss library design, screening and fragment to lead processes. Case studies will be presented for two challenging targets, BACE-1 and Bcl-2.

2:00 Mapping Binding Site Volumes: Potential Applications Towards the Design of Selective Ligands
Nidhi Arora, Ph. D., Research Scientist II, Roche Palo Alto LLC. R
Residues lining the binding pocket define a unique volume of the ligand binding site. Mapping the binding pockets alone would allow us to determine the “protein’s perspective” of the ideal shape and expected interactions of a potential inhibitor [Hypothesis]. Differences in binding sites of related proteins can then be explored to identify regions for targeting selectivity. Herein, we describe a method for rapid identification of binding sites using the alpha spheres methodology of MOE, followed by mapping of the binding site volume graphically as well as numerically. The graphical “volume map” defines the volume available to a potential ligand. This volume map can be enhanced through color coding to an “interaction map”, that defines the expected interaction types (i.e. hydrophobic, electrostatic etc.) that ligand atoms need to conform to, in order to achieve complementarity with the receptor. Comparison of the volume maps of related proteins allows identification of unique regions that can be exploited to achieve selectivity. We exemplify the application of the above concept towards the design of selective kinase inhibitors.

2:30 Ligand Placement into Electron Density Using PrimeX
Jeffrey A. Bell, PrimeX Product Manager, Schrödinger Inc.
Crystallographic binding experiments for drug-like fragments can be aided significantly by automated placement of ligands into binding sites observed in electron density maps. The primary goal of any such program for ligand placement is, of course, to find the conformation and position of the ligand model that best fits the electron den-sity. PrimeX, Schrödinger’s protein crystal structure refinement program, also employs information about the chemical complementarity of ligand with protein, as interpreted by the well-validated program Glide. This approach to ligand placement has been applied to a large set of protein-ligand complexes. The degree of accuracy achieved for ligand placement will be presented, and the effects of considering chemical interactions during ligand placement will be discussed.

3:00 Selected Oral Poster Presentation
Noncovalent Mass Spectrometry in Structure- and Fragment- Based Drug Discovery
Denis Zeyer, Ph.D., Head, Structural Biology, AliX
For more information please see presenter and poster in exhibit hall.

3:15 Networking Refreshment Break, Poster and Exhibit Viewing

4:00 Docking Small Molecule Inhibitors at the Interfaces of the Bcl-Xl, MDM2 and IL-2 Proteins
Volker Helms, Ph.D., Chair of Computational Biology, Center for Bioinformatics, University of Saarland
A pocket detection protocol based on molecular dynamics simulations started from crystal structures of the apo proteins solvated in water or methanol successfully identified transient pockets on the protein surfaces of BCL-XL, IL-2, and MDM2. The docking package AutoDock could then successfully place inhibitor molecules into these transient pockets with less than 2 A rms deviation from their crystal structures, suggesting this protocol as a viable tool to identify transient ligand binding pockets on protein surfaces. Recent work addresses searching side chain rotamer libraries to design pockets on protein surfaces of given size, polarity and shapes.


Fragments to Drugs
Moderator: David Bailey, Ph.D., CEO, IOTA Pharmaeuticals, Ltd.
The panel will discuss what can be learned from industry experience to date in advancing fragment hits to bona fide leads and drug candidates. The discussion will address questions such as:

What approaches have proven more or less successful for identifying and validating the most advanceable fragment hits?

  • What does a good fragment hit look like?
  • To what extent (if at all) does a fragment-based approach to lead ID provide an entree into new chemical or IP space?
  • In what ways are prospects for advancing fragment hits to drugs better or worse than for conventional HTS hits?
  • What is industry experience in applying fragment-based lead ID to less druggable targets, and what have we learned about protein druggability from the application of these methods?

Daniel A. Erlanson, Ph.D., Associate Director, Medicinal Chemistry, Sunesis Pharmaceuticals, Inc.
Lance Stewart, Ph.D., President, Biostructures, deCODE Chemistry & Biostructures
Roderick Hubbard, Ph.D., Senior Fellow, Research, Vernalis (R&D) Ltd

5:30 Reception and Poster Viewing in the Exhibit Hall

6:30  End of Day One

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