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

Chemical Biology & Drug Design
Darren BegleyGabriele Varani

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 as excellent binding efficiency against hTS. Relative binding orientations for both leads were modeled using AutoDock, and the most likely bound conformations were validated using experimentally derived STD-NMR binding epitope data. These ligands represent novel starting points for fragment-based drug design of non-canonical TS inhibitors, and their binding epitopes highlight important and previously unexploited interactions with conserved resi...Continue Reading

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Citations

Apr 18, 2013·Analytical and Bioanalytical Chemistry·Olivier CalaIsabelle Krimm
May 13, 2014·Analytical and Bioanalytical Chemistry·Peter FechnerJulia Widmaier
Mar 19, 2013·Molecular and Biochemical Parasitology·Ingrid B Müller, John E Hyde
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Aug 21, 2021·ACS Medicinal Chemistry Letters·Matthew D Shortridge, Gabriele Varani

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