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Editorial [Hot topic: Fragment-Based Methods in Drug Discovery: It's the Small Things that Matter (Guest Editors: Rob L.M. van Montfort and Ian Collins)]

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In the last decade fragment-based methods have become rapidly established in drug discovery and although it is too early for these approaches to have yielded a marketed drug, they have resulted in a significant number of drug candidates entering clinical trials and many more in pre-clinical development. Fragment-based methods were first successfully applied, further explored and rapidly adopted in the biotechnology and pharmaceutical industry, but due to the moderate costs of screening small libraries of simple compounds, fragment-based screening has also been enthusiastically embraced in academia. This has further enriched the thriving fragment-based drug discovery community and will foster the education of the next generations of scientists in modern drug discovery approaches.

In this special issue of Current Topics in Medicinal Chemistry on Case Histories in Fragment-based Drug Discovery we have tried to bring together articles that, as well as putting fragment-based drug discovery in its historical context and providing a current overview of the field, offer an exciting outlook of how the field could further evolve in terms of technology and its application to target classes that were until recently deemed to be difficult or unsuitable for structure-based or fragment-based approaches.

In their introduction Christophe Verlinde, Wim Hol and coworkers present an historical overview of fragment-based drug discovery (FBDD) including their own attempts on cocktail crystallography in the early 1990s, which clearly highlights the evolution of fragment-based drug discovery from the initial ideas of the 1980s to the mature field it is now. It certainly appears that a commonly used workflow for fragment screening is emerging, which involves initial hit detection using biophysical methods or high concentration biochemical assays, followed by structural characterization typically by X-ray crystallography. However, their article also shows that cocktail crystallography remains a powerful direct screening method and that it can be efficiently used in an academic structural genomics environment.

Vicki Nienaber describes how the concepts underlying FBDD can be applied to drug targets in the central nervous system which require inhibitors to cross the blood-brain barrier and thus place additional restraints on their physicochemical properties. At a time when many fragment libraries have tended to increase in average molecular weight due to the use of high concentration bioassay as a pre-filter, or to allow for including certain desirable heavy functional groups in the compounds, she and her coworkers designed a fragment library with a lower average molecular weight than a typical fragment library to help keep the physicochemical properties of their inhibitors under tight control during lead optimization. Early examples indicate that the application of FBDD to neuroscience targets shows considerable promise.

Tom Davies, Steven Woodhead and Ian Collins describe collaborative research by Astex Therapeutics and The Institute of Cancer Research aimed at designing potent and selective protein kinase B (PKB) inhibitors as antitumour agents. Their contribution shows how low affinity fragment hits were rapidly optimized to potent PKB inhibitors using a PKA-PKB chimeric protein as a surrogate system for high-throughput X-ray crystallography, which was crucial in structural characterization of the fragment hits and in guiding the medicinal chemistry in the hits-to-leads and lead optimization phases of the project. In addition, they show that selectivity of one of the inhibitor scaffolds for PKB.. over PKA could be structurally explained using protein-ligand structures of PKA, the PKA-PKB chimera and PKBβ. Moreover, inhibitors from two different chemical series showed biomarker modulation and a reduction in tumour growth in mouse xenografts, illustrating the ability to discover efficacious lead compounds with properties suitable for further development using FBDD methods.

One of the ideas adopted quickly by scientists involved in FBDD is the concept of ligand efficiency, which can be thought of as a metric for normalizing potency while accounting for the number of heavy atoms in a fragment. Such normalization shows that although fragments may bind with low affinity, for their size they are actually efficient binders. Allen Reitz and coworkers detail the use of a range of efficiency indices in assessing fragment hit quality, such as the percentage efficiency index and Fit Quality. They show that ligand efficiencies are systematically lower for larger ligands and argue that the Fit Quality index is a more consistent metric for comparing small and large compounds. In addition, they describe how FBDD ideas can be transferred to more traditional screening campaigns by applying these indices appropriately in the analysis of the screening hits.

Although fragment screening using a high concentration bioassay is becoming more popular, it is often the case that such assays are not sensitive enough to detect weakly binding fragments. In these cases one has to resort to sensitive biophysical methods for hit detection, typically NMR or X-ray crystallography. However, another biophysical technique increasingly used in fragment screening is Surface Plasmon Resonance (SPR). Helena Danielson thoroughly reviews the application of this relatively young technique in fragment screening and illustrates the experimental setup, successes and potential pitfalls with several examples. Similar to NMR and X-ray crystallography, SPR can be used in screening and may also provide valuable information in the more advanced hit-to-lead and lead optimization stages of a drug discovery project. Moreover, when used in combination with one or both of these techniques SPR could be very powerful in thoroughly characterizing the available hit matter, and more advanced inhibitors, thus accelerating the design of high quality lead compounds.

Gregg Siegal and Johan Hollander describe one of the most exciting new technologies in fragment-based drug discovery, Target Immobilised NMR Screening (TINS). This is a ligand-based NMR method which, similar to SPR, is based on the immobilization of the protein target during screening using a variety of methods. However, in the TINS method the target and a reference protein are immobilized on a resin in a dual flow-cell placed in the NMR spectrometer. Binding is detected as a reduction in peak height in a ligand NMR spectrum in the presence of target protein as compared to the reference protein. Amongst the advantages TINS has in common with SPR are the low amounts of protein required, the ability to monitor the health of the protein during the screen, and the use of reference proteins to discriminate between real hits and non-specific binders. TINS can easily be used to obtain experimental insight into the drugability of a target and can be followed up by more advanced NMR methods to further characterize the hits and determine their binding constants, as exemplified by the authors for a protein-protein interaction target. In addition they address one of the big current challenges in FBDD, which is how to progress fragment hits when protein ligand-structures are not available or are very difficult to obtain within the timeframe of a drug discovery project. The authors sketch how TINS, in combination with additional NMR approaches such as the incorporation of paramagnetic centers to obtain distance and orientation information for bound ligands, could be used to obtain low-resolution structural information to aid the elaboration of fragments into more lead-like molecules. Finally, they describe the application of TINS to membrane proteins, targets that to date have not been amenable to structure-based or fragment-based drug discovery approaches due to the difficulties in obtaining high resolution structural data. Preliminary results from a TINS screen on the membrane protein DsbB, demonstrate that the technology could in principle be applied to certain classes of membrane proteins. It will therefore be exciting to see how TINS will be applied to pharmaceutically more relevant membrane proteins such as the G protein-coupled receptors.

We hope that our selection of articles will convince you that FBDD continues to be an exciting approach in drug discovery with established utility and the promise for significant further advances. We would like to thank all the authors for their contributions. Finally we would like to thank Allen Reitz for the opportunity to put this issue together.
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Document Type: Research Article

Affiliations: Section of Structural Biology The Institute of Cancer Research 237 Fulham Road, London SW3 6JB U.K.

Publication date: December 1, 2009

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