Many examples of fragment-based approaches have been described in the literature. Here's a sampling, organised by institution:
Astex
Howard et al, Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted kinase Inhibitor with Potent Aurora Kinase Activity, J. Med. Chem. 2009, 52, 379-388 DOI | Dan's review
Wyatt et al, Identification of N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design. J. Med. Chem. 2008, 51, 4986–4999. DOI | Dan's review
Roche
Boehm et al, Novel Inhibitors of DNA Gyrase: 3D Struture Based Biased Needle Screening, Hit Validaton by Biophysical Methods, and 3D Guided Optimization. A promising Alternative to Random Screening. J. Med. Chem. 2000, 43, 2664-2674. DOI | Pete's review
Controlling the behavior of compounds and materials by manipulation of molecular properties.
Saturday, 20 December 2008
Tuesday, 2 December 2008
X-ray Crystallography
X-ray crystallography can be used to screen fragments.
Hartshorn et al, Fragment-Based Lead Discovery Using X-ray Crystallography J. Med. Chem. 2005, 48, 403-413 DOI
Nienaber et al, Discovering novel ligands from macromolecules using X-ray crystallographic screening. Nature Biotech. 2000, 18, 1105-1108. DOI
Allen et al, An Experimental Approach to Mapping the Binding Surfaces of Crystalline Proteins J. Phys. Chem., 1996, 100, 2605–2611 DOI
Hartshorn et al, Fragment-Based Lead Discovery Using X-ray Crystallography J. Med. Chem. 2005, 48, 403-413 DOI
Nienaber et al, Discovering novel ligands from macromolecules using X-ray crystallographic screening. Nature Biotech. 2000, 18, 1105-1108. DOI
Allen et al, An Experimental Approach to Mapping the Binding Surfaces of Crystalline Proteins J. Phys. Chem., 1996, 100, 2605–2611 DOI
Biochemical Assay
Biochemical assays can have high throughput and are relatively inexpensive to run.
Shapiro, Walkup and Keating Correction for Interference by Test Samples in High-Throughput Assays. J. Biomol. Screen. 2009, 14, 1008-1016 | DOI | Review
Hesterkamp et al, Fragment based drug discovery using fluorescence correlation spectroscopy techniques: Challenges and solutions. Curr. Top. Med. Chem. 2007, 7, 1582-1591 Link
Barker et al, Fragment screening by biochemical assay. Expert Opin. Drug Discov. 2006, 1, 225-236 DOI
Shapiro, Walkup and Keating Correction for Interference by Test Samples in High-Throughput Assays. J. Biomol. Screen. 2009, 14, 1008-1016 | DOI | Review
Hesterkamp et al, Fragment based drug discovery using fluorescence correlation spectroscopy techniques: Challenges and solutions. Curr. Top. Med. Chem. 2007, 7, 1582-1591 Link
Barker et al, Fragment screening by biochemical assay. Expert Opin. Drug Discov. 2006, 1, 225-236 DOI
Monday, 1 December 2008
FBDD Theory
These articles describe the theoretical basis of FBDD
Ligand Efficiency
Bembenek et al, Ligand efficiency and fragment-based drug discovery. Drug. Discov. Today, In press DOI | Mel's review
Reynolds et al, The role of molecular size in ligand efficiency. Bioorg. Med. Chem. Lett. 2007 17, 4258-61 DOI | Mel's review
Hajduk, Fragment-Based Drug Design: How Big Is Too Big? J. Med. Chem. 2006, 49, 6972-6976 DOI | Pete's review
Kuntz et al, The maximal affinity of ligands. PNAS 1999, 96, 9997-10002. Link to free article | Mel's review
Molecular Complexity
Hann, Leach & Harper, Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery. J. Chem. Inf. Comput. Sci. 2001, 41, 856-864 DOI | Pete's review
Ligand Efficiency
Bembenek et al, Ligand efficiency and fragment-based drug discovery. Drug. Discov. Today, In press DOI | Mel's review
Reynolds et al, The role of molecular size in ligand efficiency. Bioorg. Med. Chem. Lett. 2007 17, 4258-61 DOI | Mel's review
Hajduk, Fragment-Based Drug Design: How Big Is Too Big? J. Med. Chem. 2006, 49, 6972-6976 DOI | Pete's review
Kuntz et al, The maximal affinity of ligands. PNAS 1999, 96, 9997-10002. Link to free article | Mel's review
Molecular Complexity
Hann, Leach & Harper, Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery. J. Chem. Inf. Comput. Sci. 2001, 41, 856-864 DOI | Pete's review
Screening Library Literature
The first law of computation (garbage in, garbage out) applies equally well to FBDD. These articles discuss the selection of compounds for fragment screening.
Blomberg et al, Design of compound libraries for fragment screening, J. Comput.-Aid. Mol. Des., 2009, 23, 513-525 DOI
Schuffenhauer et al, Library Design for Fragment Screening. Curr. Top. Med. Chem. 2005, 5, 751-762 link
Baurin et al, Design and Characterization of Libraries for Use in NMR Screening against Protein Targets. J. Chem Inf. Comp. Sci. 2004, 44, 2157-2166 DOI
Blomberg et al, Design of compound libraries for fragment screening, J. Comput.-Aid. Mol. Des., 2009, 23, 513-525 DOI
Schuffenhauer et al, Library Design for Fragment Screening. Curr. Top. Med. Chem. 2005, 5, 751-762 link
Baurin et al, Design and Characterization of Libraries for Use in NMR Screening against Protein Targets. J. Chem Inf. Comp. Sci. 2004, 44, 2157-2166 DOI
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