Free Ligand 1D NMR Conformational Signatures To Enhance Structure Based Drug Design of a Mcl‑1 Inhibitor (AZD5991) and Other Synthetic Macrocycles

The
three-dimensional
conformations adopted by a free ligand in
solution impact bioactivity and physicochemical properties. Solution
1D NMR spectra inherently contain information on ligand conformational
flexibility and three-dimensional shape, as well as the propensity
of the free ligand to fully preorganize into the bioactive conformation.
Herein we discuss some key learnings, distilled from our experience
developing potent and selective synthetic macrocyclic inhibitors,
including Mcl-1 clinical candidate AZD5991. Case studies have been
selected from recent oncology research projects, demonstrating how
1D NMR conformational signatures can complement X-ray protein–ligand
structural information to guide medicinal chemistry optimization.
Learning to extract free ligand conformational information from routinely
available 1D NMR signatures has proven to be fast enough to guide
medicinal chemistry decisions within design cycles for compound optimization.