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Updated: Jul 12, 2025

Author Spotlight: Exploring Intrinsically Disordered Protein Dynamics Through NMR Relaxation Experiments
Published on: November 1, 2024
Nuclear magnetic resonance free ligand conformations and atomic resolution dynamics
Amber Y S Balazs1, Nichola L Davies2, David Longmire2
1Chemistry, Oncology R&D, AstraZeneca, Waltham, Massachusetts 02451, United States.
Abstract:
Knowledge of free ligand conformational preferences (energy minima) and conformational dynamics (rotational energy barriers) of small molecules in solution can guide drug design hypotheses and help rank ideas to bias syntheses towards more active compounds. Visualization of conformational exchange dynamics around torsion angles, by replica exchange with solute tempering molecular dynamics (REST-MD), gives results in agreement with high-resolution H nuclear magnetic resonance (NMR) spectra and complements free ligand conformational analyses. Rotational energy barriers around individual bonds are comparable between calculated and experimental values, making the in-silico method relevant to ranking prospective design ideas in drug discovery programs, particularly across a series of analogs. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the "right molecules" for effective medicines.
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