Fragment-Based Drug Discovery

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7:00 am Registration and Morning Coffee

8:00 Chairperson’s Opening Remarks

Roderick E. Hubbard, Ph.D., Professor, Research, Vernalis, Ltd.

8:10 Opening Presentation:
Current Challenges in Fragment-Based Discovery

Roderick E. Hubbard, Ph.D., Professor, Research, Vernalis, Ltd.

I will review current perspectives and challenges in modern fragment-based discovery including: (a). fragments and chemical space, (b). how to decide which fragments to progress and (c). methods for progressing fragments for challenging targets.

Fragment-Based Drug Discovery (FBDD) Techniques

8:50 19F NMR Fragment-Based Screening for Mapping Protein Fluorophilic Hot Spots

Anna Vulpetti, Ph.D., Global Discovery Chemistry, Novartis Institutes for Biochemical Research, Novartis Pharma AG

• Novel strategy for the design of a fluorinated fragment library, named LEF.
• 19F NMR ligand-based screening of  LEF and crystal structure determination of the hits.
• Guidelines for the selection of appropriate fluorine moieties for making the most favourable interactions with the receptor (“rule of shielding”)

9:20 Let Gibbs be Your Guide: Free Energy Simulations in Fragment-Based Drug Design

Charles Reynolds, Ph.D., Senior Director, Discovery Technologies, Ansaris

We have developed a fast free energy method for simulating the interaction of small molecule fragments with their target proteins, as well as computational methodology for linking these fragments into ligands. This approach provides an accurate and efficient means for assessing the potential binding locations and affinities for thousands of molecular fragments. As such, it is far more comprehensive than most other fragment-based approaches, especially those that rely on relatively low-throughput biophysical methods. Molecular fragments identified in this process can, in collaboration with medicinal chemistry, be used to design potent ligands with diverse molecular structures. This approach has been applied successfully to a variety of drug targets, including most recently protein-protein interactions.

9:50 Networking Coffee Break in the Exhibit Hall with Poster Viewing

10:15 Identification of Spirocyclic Pyrrolidines as Novel BACE Inhibitors by Means of X-Ray Based Fragment Screening

Ivan Efremov, Ph.D., Senior Principal Scientist, Neurosciences Chemistry, Worldwide Medicinal Chemistry, Pfizer, Inc.

X-ray based screening of the proprietary fragment collection led to identification of a novel BACE binder featuring spiropyrrolidine framework. Analysis of the binding mode and early hit expansion efforts allowed to establish a productive fragment growing direction. Hit assessment highlighted promising ligand efficiency profile and a potential for good brain penetration in more advanced analogs. Initial SAR work resulted in potency improvement from millimolar to single digit micromolar range while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.

Sponsored by
Chemical Computing Group
10:45 A Computational Approach for Performing Medicinal Chemistry Transformations within a 3D Active Site

Chris Williams, Ph.D., Principal Scientist, Chemical Computing Group

In this work, MedChem Transformations, a modeling application for performing medicinal chemistry transformations in the context of the 3D receptor and ranking the resulting molecules is presented. The methodology is outlined and a test study using a PDE5A-Sildenafil complex is performed. The results demonstrate that including pocket atoms and preserving key interactions help generate promising candidates that are relevant to the PDE5A receptor as well as a known PDE5A ligand (Vardenafil) from the original Sildenafil molecule. 

Sponsored by

11:15 Screening using Capillary Electrophoresis (CE): An Additional Tool in the Fragment Screening Toolbox

Carol Austin, Ph.D., Biology Group Leader, Discovery, Selcia Ltd.

Selcia have successfully developed a CE-based method to detect weak fragment binding interactions with soluble protein targets. Assays for several different targets, including Hsp90, have been successfully developed. Case studies will be presented.

11:30 Identification of High-Quality Fragment Leads using SPR Biosensor-Based Screening

Per Kallblad, Ph.D., CEO, Beactica AB

High-quality starting points are key to success for any fragment-based medicinal chemistry program. Case studies will be presented to exemplify how experimental design on SPR biosensors can enable the identification and optimization of fragments with desired characteristics and a defined mode of action – also for challenging targets.

12:00 pm Luncheon Presentation(Sponsorship Opportunity Available) or Lunch on Your Own

1:25 Chairperson’s Remarks 

Screening and Lead Optimization

1:30 Incorporating Medchem Expertise into Compound Library Design for Fragment-based Drug Discovery

Roman Kombarov, Ph.D., Project Manager, ASINEX

2:00 Applications of Mass Spectrometry in Fragment Library Screening

Denis Zeyer, Ph.D., CEO, Novalix

Non-covalent mass spectrometry is a biophysical method that allows detection and characterization of intact protein-compound complexes through accurate mass measurements. Combining high sensitivity and automation, this unique tool is an alternative and/or a complementary screening method compare to NMR or SPR. We will present case studies involving mass spectrometry in the fragment-based drug discovery process and compare results obtain with NMR or SPR screening methods.

    Sponsored by
2:30 Recent Advances in Structure-Based Fragment Docking and Virtual Screening

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

Fragment-based drug design continues to be a hot area of research in the pharmaceutical industry. In this work, we describe recent advances in computational docking and scoring of fragments. Specifically, we first discuss the importance of accurate tautomer and ionization state prediction. We then show that Glide docking can accurately place fragments when induced-fit of the protein is not significant. Finally, we demonstrate that Glide can enrich databases for active fragments. Since the default docking parameters typically used for drug-like molecules may not be optimal when studying fragments, we show how to improve screening results with a modified scoring function.

3:00 Sponsored Presentation (Opportunity Available)

3:15 Networking Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 Ligand Specificity in Fragment-Based Drug Design

Isabelle Krimm, Ph.D., Fragment-Based Drug Design & NMR, CNRS, University of Lyon

Fragment-Based Drug Discovery (FBDD) process consists of identifying small molecular weight compounds that weakly bind to a target macromolecule.One of the advantages to FBDD over high throughput screening is the high hit rates observed in the fragment-based screening campaigns. However, these hit rates may be due to the low specificity of the fragments, which are simple and little elaborated molecules. Using different examples published in the literature, the question of the specificity of the fragments (issue or advantage for the FBBD approach) will be discussed.

4:30 Electron Density Guided Fragment-Based Lead Discovery of Ketohexokinase Inhibitors

Marta C. Abad, Ph.D., Senior Scientist, Johnson & Johnson Pharmaceutical Research and Development

A fragment-based drug design paradigm has been successfully applied in the discovery of a lead series of ketohexokinase inhibitors. Our method uses protein crystallography as the sole detection tool for fragment-based lead discovery.  We provide results from our ketohexokinase campaign detailing the progression from initial X-ray based fragment screen to a unique lead series with promising drug-like properties.

5:00 Progress toward an Allosteric Inhibitor of HIV Protease

Charles David Stout, Ph.D., Associate Professor, Molecular Biology, The Scripps Institute

A fragment screen employing crystallography against HIV protease (PR) in the closed, inhibited form identified two surface binding sites, the exo site and the flap site, each with the potential to alter PR conformational preferences.  Based on the initial fragment hits, larger, higher affinity molecules are being developed. Such molecules could act in synergy with FDA-approved PR inhibitors, potentially via allosteric mechanisms, to restore potency against multi-drug-resistant PR mutants.

5:30 Networking Cocktail Reception in the Exhibit Hall with Poster Viewing

6:30 End of Day

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