Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 7, Number 16, 2007

Contents

Fragment-Based Drug Discovery Approaches
Guest Editors: Jeffrey Albert and Judd Berman


Editorial Pp. 1543


Fragment-Based Drug Discovery: What has it Achieved so Far? Pp. 1544-1567
Alexander A. Alex and Maria M. Flocco
[Abstract]


The SeeDs Approach: Integrating Fragments into Drug Discovery Pp. 1568-1581
Roderick E. Hubbard, Ben Davis, Ijen Chen and Martin J Drysdale
[Abstract]


Fragment Based Drug Discovery Using Fluorescence Correlation Spectroscopy Techniques: Challenges and Solutions Pp. 1582-1591
T. Hesterkamp, J. Barker, A. Davenport and M. Whittaker
[Abstract]


Practical Aspects of NMR-based Fragment Discovery Pp. 1592-1599
Edward R. Zartler and Huaping Mo
[Abstract]


An Integrated Approach to Fragment Based Lead Generation: Philosophy, Strategy and Case Studies from AstraZeneca’s Drug Discovery Programmes Pp. 1600-1629
Jeffrey S. Albert, Niklas Blomberg, Alexander L. Breeze, Alastair J. H. Brown, Jeremy N. Burrows, Philip D. Edwards, Rutger H. A. Folmer, Stefan Geschwindner, Ed J. Griffen, Peter W. Kenny, Thorsten Nowak, Lise-Lotte Olsson, Hitesh Sanganee and Adam B. Shapiro
[Abstract]


SPR-based Fragment Screening: Advantages and Applications Pp. 1630-1642
T. Neumann, H-D. Junker, K. Schmidt and R. Sekul
[Abstract]


Molecule of Month Pp. 1643




Abstracts

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Editorial

This issue of Current Topics in Medicinal Chemistry focuses on Fragment-based Drug Discovery Approaches and aims to provide readers with both an overview of major methods of the field as well as offering insights from specific case studies.

The poet Browning included “less is more” in his fabled poem to Lucrezia and this “minimalist” philosophy can readily be associated with the recent flurry of interest in fragment-based drug discovery approaches. This is exciting science! The figure below plots the number of references cited when “fragment-based” is entered as a literature search term. Interest is growing and reports of the impact of these new methods in aiding in the identification of clinical candidates against various targets have appeared. For a recent compelling review please see P.J. Hajduk and J. Greer, Nature Reviews Drug Discovery, 2007, 6(3), 211-219, A decade of fragment-based drug design: strategic advances and lessons learned.


The issue begins with a contribution by Alex et al. describing the conceptual and computational principles that serve as the theoretical basis for fragment-based approaches. With that as background, Hubbard et al. then present a clear description of a combination of experimental approaches to reducing the broad concepts to an implemented reality. Hesterkamp et al. overviews a variety of biophysical approaches and describes their use of Fluorescence Correlation Spectroscopy techniques with specific application to the discovery of inhibitors of prostaglandin D synthase. Zartler and Mo offer a discussion of the practical aspects of NMR-based fragment discovery. AstraZeneca contributes their approaches to fragment-based lead generation with selected examples. Neumann et al. describe their work with chemical microarrays of fragments and surface plasmon resonance detection methods with application to thrombin and PDE.

The interested reader should also be aware of the superb monograph edited by Erlanson and Jahnke entitled Methods and Principles in Medicinal Chemistry (2006), 34 (Fragment-Based Approaches in Drug Discovery).

It has been our pleasure to work with the contributors to this issue and with Dr. Allen Reitz and the Bentham team. Enjoy!


Jeffrey Albert
AstraZeneca
jeffrey.albert@astrazeneca.com

Judd Berman
Dalton Medicinal Chemistry Partners
jberman@dalton.com


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Fragment-Based Drug Discovery: What has it Achieved so Far?
Alexander A. Alex and Maria M. Flocco

Fragment-based drug discovery has proved to be a very useful approach particularly in the hit-to-lead process, providing a complementary tool to traditional high-throughput screening. Although often synonymous with fragment screening, fragment-based drug discovery is a far wider area covering high-throughput screening, fragment screening and virtual screening efforts. The unifying feature of fragment-based drug discovery is the low molecular weight of the hit rather than the approach it originates from. Over the last ten years, fragment-based drug discovery has provided in excess of 50 examples of small molecule hits that have been successfully advanced to leads and therefore resulted in useful substrate for drug discovery programs. To our knowledge, there are currently no marketed drugs that can be attributed to these efforts. However, due to the time scales of drug discovery and development it is likely that over the next few years the number of such examples will increase significantly.


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The SeeDs Approach: Integrating Fragments into Drug Discovery
Roderick E. Hubbard, Ben Davis, Ijen Chen and Martin J Drysdale

Finding novel compounds as starting points for optimization is a major challenge in drug discovery research. Fragment-based methods have emerged in the past ten years as an effective way to sample chemical diversity with a limited number of low molecular weight compounds. The structures of the fragments(s) binding to the protein can then be used to design new compounds with increased affinity, specificity and novelty. This article describes the Vernalis approach to fragment based drug discovery, called SeeDs (Structural exploitation of experimental Drug startpoints). The approach includes the design of a fragment library, identification of fragments that bind competitively to a target by ligand-based NMR techniques and protein crystal structures to characterize binding. Fragments that bind are then evolved to hits, either by growing the fragment or by combining structural features from a number of compounds. The process is illustrated with examples from recent medicinal chemistry programmes to discover compounds against the oncology targets Hsp90 and PDK1. In addition, we summarise our experience with using molecular docking calculations to predict fragment binding and anecdotes on the selectivity and binding modes for fragments seen against a range of targets.


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Fragment Based Drug Discovery Using Fluorescence Correlation Spectroscopy Techniques: Challenges and Solutions
T. Hesterkamp, J. Barker, A. Davenport and M. Whittaker

Novel starting points for medicinal chemistry programmes can be effectively identified by screening libraries of fragment molecules in biochemical assays at high concentration. The key to success with this approach is the combination of a high quality fragment library with sensitive biochemical screening methods. There are an increasing number of literature reports where weakly active fragment molecules have been identified by high concentration biochemical assays. We have successfully demonstrated the use of high concentration screening of fragments, using a portfolio of single-molecule Fluorescence Correlation Spectroscopy (FCS+plus) detection techniques to ensure the highest reproducibility and sensitivity, and have determined the binding mode of active fragments to target proteins by X-ray crystallography. Further biophysical detection methods are reviewed for their applicability to studies of fragment binding.


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Practical Aspects of NMR-based Fragment Discovery
Edward R. Zartler and Huaping Mo

Fragment-based drug discovery (FBDD) needs a biophysical assay to complement, or even replace, biochemical screening. NMR is the best choice for this because NMR delivers many different types of data that impacts medicinal chemistry decisions. There are a multitude of different NMR methods which can be employed to these ends. The choice of which method to use will be different for every need. We discuss the different methods, the data they produce, and how they are best utilized in a FBDD setting.


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An Integrated Approach to Fragment Based Lead Generation: Philosophy, Strategy and Case Studies from AstraZeneca’s Drug Discovery Programmes
Jeffrey S. Albert, Niklas Blomberg, Alexander L. Breeze, Alastair J. H. Brown, Jeremy N. Burrows, Philip D. Edwards, Rutger H. A. Folmer, Stefan Geschwindner, Ed J. Griffen, Peter W. Kenny, Thorsten Nowak, Lise-Lotte Olsson, Hitesh Sanganee and Adam B. Shapiro

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. In comparison to HTS screening libraries, the screening sets for FBLG tend to contain orders of magnitude fewer compounds, and the compounds themselves are less structurally complex and have lower molecular weight. This report summarises the advent of FBLG within the industry and then describes the FBLG experience at AstraZeneca. We discuss (1) optimising the design of screening libraries, (2) hit detection methodologies, (3) evaluation of hit quality and use of ligand efficiency calculations, and (4) approaches to evolve fragment-based, low complexity hits towards drug-like leads. Furthermore, we exemplify our use of FBLG with case studies in the following drug discovery areas: antibacterial enzyme targets, GPCRs (melanocortin 4 receptor modulators), prostaglandin D2 synthase inhibitors, phosphatase inhibitors (protein tyrosine phosphotase 1B), and protease inhibitors (b-secretase).


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SPR-based Fragment Screening: Advantages and Applications
T. Neumann, H-D. Junker, K. Schmidt and R. Sekul

Fragment-based screening has recently evolved into a promising strategy in drug discovery, and a range of biophysical methods can be employed for fragment library screening. Relevant approaches, such as X-ray, NMR and tethering are briefly introduced focussing on their suitability for fragment-based drug discovery. In particular the application of surface plasmon resonance (SPR) techniques to the primary screening of large libraries comprising small molecules is discussed in detail. SPR is known to be a powerful tool for studying biomolecular interactions in a sensitive and label-free detection format. Advantages of SPR methods over more traditional assay formats are discussed and the application of available channel and array based SPR systems to biosensing are reviewed. Today, SPR protocols have been applied to secondary screening of compound libraries and hit conformation, but primary screening of large fragment libraries for drug discovery is often hampered by the throughput of available systems. Chemical microarrays, in combination with SPR imaging, can simultaneously generate affinity data for protein targets with up to 9,216 immobilized fragments per array. This approach has proven to be suitable for screening fragment libraries of up to 110,000 compounds in a high throughput fashion. The design of fragment libraries and appropriate immobilization chemistries are discussed, as well as suitable follow-up strategies for fragment hit optimization. Finally, described case studies demonstrate the successful identification of selective low molecular weight inhibitors for pharmacologically relevant drug targets through the SPR screening of fragment libraries.