Journal of Proteomics & Bioinformatics
Open Access
ISSN: 0974-276X
ISSN: 0974-276X
Judith Reeks
Astex Pharmaceuticals, UK
Posters & Accepted Abstracts: J Proteomics Bioinform
Fragment-based drug discovery at Astex uses X-ray crystallography and orthogonal biophysical techniques (including NMR, SPR, ITC and thermal shift) to detect the binding of low molecular weight fragments (<300 Da) to proteins. Although the detected fragment �??hits�?? bind weakly (mM), their small size permits the formation of optimal interactions with the target protein and the fragments serve as valuable starting points for rational drug design. Hits with good growth vectors can be chemically elaborated into potent ligands through fast, iterative rounds of structure-based design. This approach allows for the control, and optimisation, of ligand potency, selectivity, and physicochemical properties. This poster will describe the key aspects of fragment-based drug discovery at Astex, illustrated by the fragment screening that led to potent, selective inhibitors of ERK1/2. Recent Publications: 1. Tan Y S, Reeks J et al. (2016) Benzene probes in molecular dynamics simulations reveal novel binding sites for ligand design. Journal of Physical Chemistry Letters 7:3452-7. 2. Reeks J et al. (2013) Structure of the archaeal Cascade subunit Csa5: relating the small subunits of CRISPR effector complexes. RNA Biology 10:762-9. 3. Reeks J et al. (2013) CRISPR interference: a structural perspective. Biochemical Journal 453:155-166. 4. Reeks J et al. (2013) Structure of a dimeric crenarchaeal Cas6 enzyme with an atypical active site for CRISPR RNA processing. Biochemical Journal 452:223-230. 5. Zhang et al. (2012) Structure and mechanism of the CMR complex for CRISPR-mediated antiviral immunity. Molecular Cell 45:303-313.