Fragment-based Drug Discovery

Fragment-based drug discovery (FBDD) is a rapidly emerging field to identifying novel, small molecule, preclinical development candidates. Because traditional high-throughput screening has had its challenges, due to the complexity and relatively large size of the compounds routinely being screened, FBDD had been gaining momentum as an alternative approach. It starts with very small, low molecular weight, drug fragments which have the potential to keep the overall complexity and molecular weight of each drug candidate low. Traditional bioassays are not able to detect small drug fragments because of their low potency binding to the protein target. Thus, FBDD integrates biophysical techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, isothermal calorimetry with fragment library design and a range of computational methodologies for an efficient hit-to-lead process. The ultimate success of any drug discovery program is measured by the quality and quantity of the drugs it produces. FBDD has been practical in the past decade only, thus too soon to put its stamp yet on marketed drugs. However, we have faith that it will indeed deliver on its promise.

On 17 October 2007 we will hold an eCheminfo Community of Practice conference session at Bryn Mawr College, Philadelphia to discuss latest advances in fragment-based drug discovery. The session will be chaired by Maria Kontoyianni and includes a knowledgeable panel of speakers and discussion leaders: Chaohong Sun (Abbott), Renate Sekul (Graffinity), Woody Sherman (Schrodinger), Georgia McGaughey (Merck) and Stephen Burley (SGX Pharmaceuticals). A description of the session with presentation abstracts follows:

Fragment-based Drug Discovery
http://echeminfo.com/COMTY_conferencesprog07fragment

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Abstracts

NMR in target profiling and compound file enhancement
Chaohong Sun, Abbott Laboratories

NMR has matured as an important tool in drug discovery and development, with its roles in lead generation and optimization through NMR-based fragment screening and structure based drug design being well established. Besides these applications, NMR has expanded to make contributions both earlier and later in the drug discovery process. Here, the impact of NMR in the early stages of drug discovery will be presented, in particular in profiling targets and in using fragment hits in compound file-enhancement initiatives.

Fragment based discovery by SPR imaging of chemical microarrays
Renate Sekul, VP R&D at Graffinity Pharmaceuticals, Germany

Fragment-based screening has evolved into a promising strategy in drug discovery. Surface plasmon resonance (SPR) is known to be a powerful tool for studying biomolecular interactions in a sensitive and label-free format. Graffinity´s SPR imaging of chemical microarrays can simultaneously generate affinity data for protein targets with up to 9,216 immobilized fragments per array. The detection sensitivity allows the identification of weak interactions and is therefore particularly suited for fragment screening. Selected case studies demonstrate the successful identification of low molecular weight inhibitors for pharmacologically relevant targets.

 

Using fragments to couple ligand- and structure-based approaches.
Woody Sherman, Schrodinger

We have developed a method to generate structure-based pharmacophore hypotheses derived from the results of fragment docking. The quality of the results depends heavily on the ability of docking algorithm to accurately dock and score small fragments within the binding pocket. We first show that Glide XP is able to accurately dock and score fragments. We then describe the methodology used to generate chemically meaningful structure-based pharmacophore hypotheses that can be used in database searching. Results from database enrichment screens will be shown where good enrichments are obtained with the structure-based pharmacophore hypotheses and novel compounds are proposed based on the database screens.

 

Design of Beta-secretase (BACE-1) inhibitors through in silico property-based fragment scanning
Georgia B. McGaughey (1), J. Christopher Culberson (1), Bradley P. Feuston (1), Simon K. Kearsley (2), Ralph Mosley (2) and M. Katharine Holloway (1)
Merck Research Laboratories
(1) Molecular Systems Department, P.O. BOX 4, West Point, PA 19486
(2) Molecular Systems Department, P.O. BOX 2000, Rahway, NJ 07065

Beta-Secretase (BACE-1) is a transmembrane aspartyl protease intimately involved in the neurodegenerative disorder, Alzheimer’s disease. With a significant amount of in-house structural knowledge of BACE-1, chemotype-specific scoring functions for rank-ordering virtual compounds have proven useful for explaining structure activity relationships. In advance of rank-ordering virtual compounds, scoring functions were evaluated for a series of tertiary carbinamine inhibitors to obtain a correlation with the experimentally determined Ki values. These inhibitors were examined in crystallographic complexes with BACE-1 which revealed 10s loop motion in the S3 pocket. Combining these scoring functions with Merck’s unique virtual compound library tools provided an opportunity for focused library designs which directly impact lead finding/optimization in a timely manner. To facilitate the design and optimization of virtual BACE-1 compound libraries, Merck’s Virtual Library ToolKit (VLTK) has been enhanced to include 3D library construction. This presentation will focus on the various aspects of focused library designs and specifically, the application to BACE-1 inhibitors.

 

Fragment-based discovery of selective, orally bioavailable tyrosine kinase inhibitors for targeted treatment of human cancers
Stephen K. Burley, Chief Scientific Officer and Senior Vice-President Research, SGX Pharmaceuticals, Inc., 10505 Roselle Street, San Diego, CA 92121

SGX Pharmaceuticals, Inc. (SGX) has developed a fragment based drug discovery platform that utilizes high-throughput X-ray crystallography for lead identification/optimization. The proprietary FAST™ (Fragments of Active Structures) process exploits crystallographic screening to detect, visualize, and identify small ligands (MW 150-200) that are bound to the target protein. Each member of the FAST™ fragment/scaffold library was selected to be amenable to rapid chemical elaboration at two or three points of chemical diversity using parallel organic synthesis. Initial lead optimization involves using our knowledge of the co-crystal structure of the target-fragment complex and advanced computational chemistry tools to guide synthesis of small focused linear (one-dimensional) libraries. These linearly elaborated fragments/scaffolds are then evaluated with in vitro biochemical and cellular assays and co-crystal structure determinations. Thereafter, optimal variations at each point of chemical diversity are combined to synthesize focused combinatorial (two- or three-dimensional) libraries that are again examined with assays and crystallography. (The potential chemical diversity of the fully elaborated FAST™ fragment/scaffold library far exceeds 160 million compounds.) Active compound series are prioritized for further medicinal chemistry and compound development efforts using the results of in vitro and in vivo ADME and in vitro toxicology studies. Successful applications of the FAST™ fragment-based lead discovery/optimization process will be presented for a portfolio of well validated oncology targets.

 

Barry Hardy
eCheminfo Community of Practice

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