Corporate Profile
Fragment-based drug discovery maturing?
By Jan Hörling, GE Healthcare I
n the last 20 years or so the majority of drug discovery programmes have used high throughput screening (HTS), ie a more or less random approach, to identify suitable chemical starting points or hits. During the late 1990s com- pound libraries grew bigger as the technol- ogy evolved to permit larger screening sets. This HTS evolution went hand-in-hand with the technology drive for liquid han- dling, robotics, compound storage and assay development. The major driving force was probably the perception that previously-used empirical and rational methods were not sufficiently successful. Now it is apparent that large scale HTS campaigns were not only expensive, but also occasionally failed to deliver useful hits. Consequently, drug discovery scien- tists are increasingly using either more sophisticated HTS with tailored com- pound libraries, rational structure-based drug design, or fragment-based drug dis- covery (FBDD).
The idea of FBDD is to circumvent some of the inherited limitations in HTS screen- ing. Instead of screening compounds that are already drug like in size and properties, smaller molecular entities, or fragments, are screened instead. Using the fragment’s inherent promiscuity due to its size, the interaction with the protein surface can be explored with significantly greater accura- cy than is possible for larger compounds. This enhances the opportunity to identify novel starting points. In addition, these fragment structures or scaffolds are poten- tially outside the often very crowded patent spaces, eg for kinases.
Although FBDD is not a new approach 50
and originally only attracted select bio- physicists, it is now well recognised as being an important part of the drug discov- ery tool box. The paradigm shift from tra- ditional high throughput screening towards more rationale, design intensive approach- es, enabled by structural biology and the fact that the technology has developed con- siderably over the last decade, has spurred the enthusiasm. The number of publica- tions and reports from both academic and pharmaceutical groups is increasing and there are now several preclinical and clini- cal candidates that were derived from FBDD approaches. Recently we witnessed the approval by the FDA of the first frag- ment-based drug. The story of Zelboraf (vemurafenib or PLX4032), shows how rapidly fragments can be developed into drugs; which in this case took just six years to reach approval. It also demonstrates how an unselective fragment can be devel- oped into a very selective drug. One of the major challenges with FBDD, compared to traditional HTS, is the reliable identification of the fragments interacting with the target of interest. Despite the high ligand efficiency, the interaction is normal- ly very weak which makes it difficult to dis- cern whether the interaction is specific or just random. Many biophysical technolo- gies are used in the initial screening phase in FBDD. The most commonly used
methodologies are NMR, X-ray chrystal- lography, fluorescence spectroscopy and surface plasmon resonance (SPR). No sin- gle method delivers all the required infor- mation to minimise false positives or nega- tives, therefore, orthogonal methods have to be used to help ensure reliable results. Label-free biosensor technologies, such as SPR, have the advantage over structure based methods as they provide more rapid information regarding specificity and con- sume considerably less target protein and require fewer compounds. As the fragment libraries are typically 1-2,000 compounds in size, throughput limitations are less and instruments such as the SPR-based Biacore 4000 can readily handle the level of throughput required.
www.gelifesciences.com/biacore
GE, imagination at work, and GE mono- gram are trademarks of General Electric Company.
Biacore is a trademark of GE Healthcare companies.
© 2012 General Electric Company – All rights reserved.
First published January 2012. Drug Discovery World Winter 2011/12
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