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Fragment-Based Drug Discovery 2009


 Day 1 - Day 2 - Download Brochure 



Monday, April 6

7:00 am Registration and Morning Coffee


8:00 Chairperson’s Opening Remarks
Andreas Kuglstatter, Ph.D., Head of Protein Crystallography, Roche Palo Alto

Improving Results – All Things Considered

In Silico Fragment-Based Drug Design

Eric Springman, Ph.D., Head of Discovery, Locus Pharmaceuticals


In silico simulation of fragment-protein interactions could in principle provide advantages in terms of the ultimate number and diversity of fragments accessible. The potential of an in silico approach relies heavily, however, on the ability to quantitate fragment binding affinities so that the molecules that are ultimately synthesized have a high probability of being active. As a first step in realizing this capability, we have described a method for rapidly computing the gas phase interaction free energies of molecular fragments with proteins. In order to extend this capability to drug design it is also necessary to compute the change in free energy when fragments are assembled into full-sized molecules, the translation of binding affinities from the gas phase to the aqueous phase, and the effects of protein flexibility. In this presentation, we will present case studies that demonstrate solutions to each of these problems and give insights into those situations in which solvation and protein flexibility, in particular, will play a major role and those cases where the roles are minor.


8:50 Fragment-Based Screening using libraries in-silico and X-Ray Crystallography

Kal Ramnarayan, Ph.D., President and Chief Scientific Officer, Sapient Discovery, LLC

Selection of fragments prior to screening is a crucial step if Fragment-Based Lead Discovery has to be successful. Too often, when random libraries are screened, the resulting hits are mostly hydrophobic/promiscious compounds that are not amenable for Lead Optimization. We use a computational pre-selection criteria to filter out fragments to be more drug-like, have enough synthetic handles with reasonable chemistry to make the novel ligand from fragments. The pre-selection also cuts down the number of compounds to be used for crystallization trials, hence saving time and resources. We will discuss our methodology with specific examples of our successes.


9:20 Virtual Fragment Linking: An Approach to Identify Potent Binders from Low Affinity Fragment Hits

Meir Glick, Ph.D., Research Investigator II, Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Inc.

In this work we explore the possibilities of using fragment-based screening data to prioritize compounds from a full HTS library, a method we call virtual fragment linking (VFL). The ability of VFL to identify compounds of nanomolar potency based on micromolar fragment binding data was tested on 75 target classes from the WOMBAT database and succeeded in 57 cases. Further, the method was demonstrated for seven drug targets from in-house screening programs that performed both FBS of 8800 fragments and screens of the full library. VFL captured between 28% and 67% of the hits (IC50 < 10µM) in the top 5% of the ranked library for four of the targets (enrichment between 5-fold and 13-fold).

9:50 Networking Coffee Break

Fragments to Leads – Case Studies

10:15 Fragment-Based Drug Discovery - from Crystal to Clinic

Gordon Saxty, Ph.D., Senior Research Associate, Astex Therapeutics Ltd.

Fragment-based approaches to lead discovery are gaining interest in many labs as a complementary approach to high-throughput screening. The presentation will include several Medicinal Chemistry Case Studies going from Fragment Hits to the Clinical compounds.

10:45 Recent Lessons in Fragment-Based Discovery

Roderick Hubbard, Ph.D., Senior Fellow, Research, Vernalis (R&D), Ltd.
We have developed and applied methods in fragment-based discovery for over eight years. I will discuss some of the recent lessons which are influencing the further development of our SeeDs approach:

  • implications for library design from an analysis of fragment hit rates across targets
  • robust validation of fragment binding for protein-protein interaction targets
  • the value of fragment derived information in lead optimisation

  Bridging the Gap between Ligand- and Structure-Based Drug Design through the Application of Pharamophcores Derived from Fragment Docking
Presentation Sponsored by Schrodinger 

Noeris Salam, Ph.D., Application Scientist, Schrodinger, Inc.
Computer-aided drug design is a valuable tool for drug discovery and can contribute to greater efficiency in finding novel hits, leads, and optimized compounds. Here, we report a novel method that unites two computational strategies: ligand- and structure-based, through the use of pharmacophore hypotheses derived from fragment docking. This methodology uses an atomic breakdown of the energetics from docking of fragments to locate key molecular features responsible for high binding affinity. First, we show that the docking program Glide consistently docks fragments in a pose similar to the experimental structure, with root mean squared deviation (RMSD) of less than 1.0 Å to known crystal structures. We then show that Glide XP energetic analysis of docked
fragments works well for selecting pharmacophore features that are consistent with known tight binding compounds. Finally, we describe the methodology that bridges structure-based fragment docking, detailed energetic pharmacophore feature analysis, and ligand-based pharmacophore database screening into a single automated protocol. We find that the hybrid method produces viable pharmacophore hypotheses that are consistent with known active compounds. The method is shown to enrich a databased for active compounds in a virtual screen.

11:30 Fragment-Based Drug Discovery by NMR: Reaping the Benefits of Orthogonal Screening Approaches to ValiDate Hit Compounds
Sponsored Presentation by Evotec
Jan D. Kahmann, Ph.D., Evotec NMR Screening
With increased sensitivity and more refined procedures NMR spectroscopy has become a robust and valuable tool for the screening of fragments binding to target proteins. The unique advantages of employing this solution based, information-rich, direct binding assay technique at the early stage of drug discovery far outweigh the limited throughput of this approach.Kinases are one of the most prominent classes of proteins for target-based drug discovery. They undergo conformational switching between activation states that are not well defined by protein crystallography. In order to identify novel ligands for specific subsites and kinase conformations we have used both ligand-observed and protein-observed (TROSY) NMR techniques to screen several kinases. The combination of orthogonal data from NMR based screening, X-ray crystallography as well as NMR data obtained on selectively isotope labelled kinase protein expressed from insect cells has given valuable clues for the development of leads from fragment based drug discovery. We will detail the NMR screening approach focussed on an allosteric binding site of a kinase isoform unique to a certain cell type.

12:00 pm Luncheon Presentation or Lunch on Your Own

1:00 Session Break

1:25 Chairperson’s Remarks
Roderick Hubbard, Ph.D., Senior Fellow, Research, Vernalis (R&D), Ltd.

Applied FBDD

1:30 Fragment-Based Screening of Antibacterial Targets

Igor Mochalkin, Ph.D., PMP, EMS - Computational Sciences, Pfizer

2:00 Presentation

2:30 Assessment of Additive/Non-Additive Effects in SAR: Implications in the Drug Discovery Iterative Process

Julen Oyarzabal, Head of Drug Discovery Informatics Section, Medicinal Chemistry. Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO).

Our aims are to determine if we can estimate which effects, additive or non-additive, are taking place in near complete libraries for the biological response(s) under study and then to determine the minimum attributes of a data set necessary to reach the same conclusion about additive/non-additive effects and, therefore, identify additive and non-additive fragments. This analysis leads us to question the concept of fragments additivity that is widely taken for granted in drug discovery.

3:00 Selected Oral Poster Presentation

3:15 Networking Refreshment Break in Exhibit Hall

4:00 Impact of Fragment Screening on the Rapid Discovery of Novel and Selective Protein Kinase Inhibitors

Andreas Kuglstatter, Ph.D., Head of Protein Crystallography, Roche Palo Alto

Crystal structures of a protein drug target in complex with small molecule fragments facilitate and accelerate drug discovery in many ways. At Roche, fragments bound to the protein kinases BTK, IRAK4 and p38α were used to (a) identify unique protein conformations that allow rational selectivity design, (b) create libraries of novel kinase inhibitors, and (c) rapidly discovery drug candiDates by hit expansion and scaffold hopping.

4:30 Panel Discussion:
The Challenge of Turning Leads Into Results

Alex Kiselyov, Ph.D., Director of Chemistry, deCODE chemistry & biostructures

Andreas Kuglstatter, Ph.D., Head of Protein Crystallography, Roche Palo Alto

Gordon Saxty, Ph.D., Senior Research Associate, Astex Therapeutics Ltd.

Kal Ramnarayan, Ph.D., President and Chief Scientific Officer, Sapient Discovery, LLC

Eric Springman, Ph.D., Head of Discovery, Locus Pharmaceuticals

5:30 Reception in the Exhibit Hall

6:30 End of day


For more information on speaking opportunities :
Margit Eder, Ph.D., Conference Director
Cambridge Healthtech Institute
Phone: 781-972-5478

For Sponsor and Exhibit Information:
Suzanne Carol, Business Development Manager
Cambridge Healthtech Institute
Phone: 781-972-5452