TY - JOUR
T1 - A fragment-based approach to probing adenosine recognition sites by using dynamic combinatorial chemistry
AU - Scott, D.E.
AU - Dawes, G.J.
AU - Ando, M.
AU - Abell, C.
AU - Ciulli, Alessio
N1 - MEDLINE® is the source for the MeSH terms of this document.
PY - 2009/11/23
Y1 - 2009/11/23
N2 - A new strategy that combines the concepts of fragment-based drug design and dynamic combinatorial chemistry (DCC) for targeting adenosine recognition sites on enzymes is reported. We demonstrate the use of 5'-deoxy-5'- thioadenosine as a noncovalent anchor fragment in dynamic combinatorial libraries templated by Mycobacterium tuberculosis pantothenate synthetase. A benzyl disulfide derivative was identified upon library analysis by HPLC. Structural and binding studies of protein-ligand complexes by X-ray crystallography and isothermal titration calorimetry informed the subsequent optimisation of the DCC hit into a disulfide containing the novel meta-nitrobenzyl fragment that targets the pantoate binding site of pantothenate synthetase. Given the prevalence of adenosine-recognition motifs in enzymes, our results provide a proof-of-concept for using this strategy to probe adjacent pockets for a range of adenosine binding enzymes, including other related adenylate-forming ligases, kinases, and ATPases, as well as NAD(P)(H), CoA and FAD(H) binding proteins.
AB - A new strategy that combines the concepts of fragment-based drug design and dynamic combinatorial chemistry (DCC) for targeting adenosine recognition sites on enzymes is reported. We demonstrate the use of 5'-deoxy-5'- thioadenosine as a noncovalent anchor fragment in dynamic combinatorial libraries templated by Mycobacterium tuberculosis pantothenate synthetase. A benzyl disulfide derivative was identified upon library analysis by HPLC. Structural and binding studies of protein-ligand complexes by X-ray crystallography and isothermal titration calorimetry informed the subsequent optimisation of the DCC hit into a disulfide containing the novel meta-nitrobenzyl fragment that targets the pantoate binding site of pantothenate synthetase. Given the prevalence of adenosine-recognition motifs in enzymes, our results provide a proof-of-concept for using this strategy to probe adjacent pockets for a range of adenosine binding enzymes, including other related adenylate-forming ligases, kinases, and ATPases, as well as NAD(P)(H), CoA and FAD(H) binding proteins.
UR - http://www.scopus.com/inward/record.url?scp=73149092359&partnerID=8YFLogxK
U2 - 10.1002/cbic.200900537
DO - 10.1002/cbic.200900537
M3 - Article
C2 - 19827080
AN - SCOPUS:73149092359
SN - 1439-4227
VL - 10
SP - 2772
EP - 2779
JO - ChemBioChem
JF - ChemBioChem
IS - 17
ER -