Coenzyme A pathway
We have a long term interest in the enzymology of Coenzyme A, both the pathway up to pantothenate (vitamin B5)
(present in plants, microorganisms and fungi) and the pathway from pantothenate to Coenzyme A (present in all cells)
[Nat. Prod. Rep. 2004].
Our research in this area is in collaboration with Professor Alison Smith (Plant Sciences) and
Professor Tom Blundell (Biochemistry).
We have a specific interest in targeting the coenzyme A pathway enzymes from Mycobacterium tuberculosis. We are using a range of biophysical
techniques including thermal shift, NMR spectroscopy, ITC and X-ray crystallography to identify molecular fragments that bind to these enzymes.
These fragments act as starting points for elaboration to potent enzyme inhibitors (see section on Fragment-based approaches to enzyme inhibitors).
We described a fragment-based approach to the development of inhibitors of M. tuberculosis pantothenate synthetase, using fragment linking
and fragment growing strategies
[Angew. Chemie Intl. Ed. 2009] and exploration of group efficiencies
|Cross section of active site of M. tuberculosis pantothenate synthetase with two fragments bound (millimolar affinity), and with micromolar inhibitor made by linking them.
||Optimization of inhibitors of Mycobacterium tuberculosis pantothenate synthetase based on group efficiency analysis|
A W Hung, H L Silvestre, S Wen, G P George, J Boland, T L Blundell, A Ciulli, C Abell
||Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery
H L Silvestre, T L Blundell, C Abell, A Ciulli
Proc. Natl. Acad. Sci. U.S.A, 2013, 110, 12984-9
|| Optimisation of the interligand Overhauser effect for fragment linking: application to inhibitor discovery against Mycobacterium tuberculosis pantothenate synthetase.|
P Sledź, H L Silvestre, A W Hung, A Ciulli, T L Blundell & C Abell
J. Am. Chem. Soc. 2010, 132, 4544-4545.
||Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase.|
A W Hung, H L Silvestre, S Wen, A Ciulli, T L Blundell & C Abell
Angew. Chemie Intl. Ed. 2009, 48, 8452-8456.