NMR free ligand conformations and atomic resolution dynamics

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 1H 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 analogues. Prioritizing design ideas, based on calculations and analysis of measurements across a series, efficiently guides rational discovery towards the right molecules for effective medicines.