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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 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.

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.

The acyl‐binding UNC119 proteins mediate the activation and transport of various N‐myristoylated proteins. In particular, UNC119a plays a crucial role in the completion of cytokinesis. Herein, we report the use of a lipidated peptide originating from the UNC119 binding partner Gnat1 as the basis for the design of lipidated, stabilized α‐helical peptides that target UNC119a. By using the hydrocarbon peptide‐stapling approach, cell‐permeable binders of UNC119a were generated that induced the accumulation of cytokinetic and binucleated cells; this suggests UNC119a as a potential target for the inhibition of cytokinesis., Targeting molecular chaperones: Cell‐permeable peptidomimetics of a myristoylated peptide were obtained by hydrocarbon peptide stapling. These agents target the human acyl‐binding protein UNC119a, which plays a crucial role in cytokinesis, inducing the accumulation of cytokinetic and binucleated cells. This suggests UNC119a as a potential target for the inhibition of cytokinesis.