Saturday, 20 December 2008

FBDD: Examples

Many examples of fragment-based approaches have been described in the literature. Here's a sampling, organised by institution:

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

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

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

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

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

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

Thursday, 20 November 2008

A few more general review articles on FBDD

Current Opinion in Chemical Biology has published several mini reviews in FBDD.  This one by the folks at Astex is short, but touches on both NMR and X-ray crystallographic approaches to FBDD:

Jhoti H, et al.  Fragment-based screening using X-ray crystallography and NMR spectroscopy.  Curr Opin Chem Biol. (2007) 11:485-493

In the same vein is a paper from Teddy Zartler at Merck that also discusses the concept of ligand efficiency in FBDD:

Zartler ER and MJ Shapiro.  Fragonomics: fragment-based drug discovery. Curr Opin Chem Biol. (2005) 9:366-370  

Tethering, an alternate approach to FBDD pioneered by Sunesis Pharmaceuticals, is discussed in this review: 

Erlanson DA and SK Hansen.  Making drugs on proteins: site-directed ligand discovery for fragment based assembly.  Curr Opin Chem Biol.  (2004) 8:399-406.

Tuesday, 11 November 2008


A variety of NMR approaches can be used to detect and quantify binding of fragments to their targets.

Lepre, Moore & Peng, Theory and Applications of NMR-Based Screening in Pharmaceutical Research Chem Rev 2004, 104, 3641-3675 DOI

Stockman & Dalvit, NMR screening techniques in drug discovery and drug design. Prog. NMR Spec. 2002, 41, 187-231. DOI

Dalvit et al, WaterLOGSY as a method for primary NMR screening: Practical aspects and range of applicability, J. Biomol. NMR 2001, 21, 349-359 DOI

Fielding, Determination of association constants (Ka) from solution NMR data, Tetrahedron 2000, 56, 6151-6170 DOI

Shuker et al, Discovering High-Affinity Ligands for Proteins: SAR by NMR, Science 1996, 274, 1531-1534 DOI

Monday, 10 November 2008

General FBDD Reviews: Pete's selections

There is plenty of review literature on FBDD and the following articles should provide a good introduction to the field.

Hesterkamp & Whittaker, Fragment-based activity space: Smaller is better. Curr. Opin. Chem. Biol. 2008, 12, 260-268. DOI

Congreve et al, Recent Developments in Fragment-Based Drug Discovery, J. Med. Chem. 2008, 51, 3661-3680 DOI

Hajduk & Greer, A decade of fragment-based drug design: strategic advances and lessons learned Nat. Rev. Drug Discov. 2007, 6, 211-219 DOI

Albert et al, An Integrated Approach to Fragment Based Lead Generation: Philosophy, Strategy and Case Studies from AstraZeneca's Drug Discovery Programs Curr. Top. Med. Chem. 2007, 7, 1600-1629 link

Erlanson et al, Fragment-Based Drug Discovery J. Med. Chem. 2004, 47, 3463-3482 DOI