Fragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping.

ABSTRACT: Solution-state nuclear magnetic resonance (NMR) is a versatile tool for the study of binding interactions between small molecules and macromolecular targets. We applied ligand-based NMR techniques to the study of human thymidylate synthase (hTS) using known nanomolar inhibitors and a library of small molecule fragments. Screening by NMR led to the rapid identification of ligand pairs that bind in proximal sites within the cofactor-binding pocket of hTS. Screening hits were used as search criteria within commercially available sources, and a subset of catalog analogs were tested for potency by in vitro assay and binding affinity by quantitative saturation transfer difference (STD)-NMR titration. Two compounds identified by this approach possess low micromolar affinity and potency, as well a

SUBMITTER: Begley DW 

PROVIDER: S-EPMC2918687 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature