Mixture-Based Screening of Focused Combinatorial Libraries by NMR: Application to the Antiapoptotic Protein hMcl‑1

We report on an innovative
ligand discovery strategy based on protein
NMR-based screening of a combinatorial library of ∼125,000
compounds that was arranged in 96 distinct mixtures. Using sensitive
solution protein NMR spectroscopy and chemical perturbation-based
screening followed by an iterative synthesis, deconvolutions, and
optimization strategy, we demonstrate that the approach could be useful
in the identification of initial binding molecules for difficult drug
targets, such as those involved in protein–protein interactions.
As an application, we will report novel agents targeting the Bcl-2
family protein hMcl-1. The approach is of general applicability and
could be deployed as an effective screening strategy for de novo identification
of ligands, particularly when tackling targets involved in protein–protein
interactions.