Medicinal chemistry has developed a rich tool box for conformational control of small molecules, including: methylation and creation of chirality, macrocyclization, atropisomerism, and the use of stereo-electronic and steric effects. Using free ligand conformational studies in drug design workflows, the first objective is to guide design hypotheses towards ligands that will adopt preferentially the bioactive conformation, eliminating potentially lower energy non-bioactive conformations. Highly stable free ligand molecular conformations that do not mimic the bioactive conformations in solution in fact, lead to ineffective ligand protein collisions and energy penalties on target binding. We showcase how to use simple 1D NMR ligand signatures and biophysical data to guide ligand conformational control designs. Specifically, we will show how we can draw Structure Kinetics Relationships when both the protein and the free ligand structural information is available.

Role of free ligand conformations in ligand binding kinetics: AstraZeneca case studies

2019 Spring National Meeting

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