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