Illuminating the dark conformational space of macrocycles using dominant rotors.

Three-dimensional conformation is the primary determinant of molecular properties. The thermal energy available at room temperature typically equilibrates the accessible conformational states. Here, we introduce a method for isolating unique and previously understudied conformations of macrocycles. The observation of unusual conformations of 16- to 22-membered rings has been made possible by controlling their interconversion using dominant rotors, which represent tunable atropisomeric constituents with relatively high rotational barriers. Density functional theory and in situ NMR measurements suggest that dominant rotor candidates for the amino-acid-based structures considered here should possess a rotational energy barrier of at least 25 kcal mol-1. Notable differences in the geometries of the macrocycle conformations were identified by NMR spectroscopy and X-ray crystallography. There is evidence that amino acid residues can be forced into rare turn motifs not observed in the corresponding linear counterparts and homodetic rings. These findings should unlock new avenues for studying the conformation-activity relationships of bioactive molecules.

De Novo Design of Boron-Based Peptidomimetics as Potent Inhibitors of Human ClpP in the Presence of Human ClpX.

Boronic acids have attracted the attention of synthetic and medicinal chemists due to boron's ability to modulate enzyme function. Recently, we demonstrated that boron-containing amphoteric building blocks facilitate the discovery of bioactive aminoboronic acids. Herein, we have augmented this capability with a de novo library design and a virtual screening platform modified for covalent ligands. This technique has allowed us to rapidly design and identify a series of α-aminoboronic acids as the first inhibitors of human ClpXP, which is responsible for the degradation of misfolded proteins.