An experimental and computational investigation of the cyclopentene-containing peptide-derived compounds: focus on pseudo-cyclic motifs via intramolecular interactions

Conformational flexibility is one of the main disadvantages of peptide-based compounds. We focus on their molecular 'chameleonicity' related to forming pseudo-cyclic motifs via modulation of weak intramolecular interactions. It is an appealing strategy for controlling equilibrium between the polar open and the nonpolar closed conformations. Within this context, we report here the crystal structure of the (<i>R</i>)-(2-<i>tert</i>-butoxycarbonyl)amino-1-oxo-3-phenyl)propyl)-1-cyclopentene (<b>1</b>), synthesis of which in high yield was achieved by a facile multi-step protocol. Our Cambridge Structural Database (CSD) overview for the peptide-based crystals revealed the exclusivity of this compound from the viewpoint of the unusual pseudo-bicyclic system via C-H^…O and C-O^…π interactions, in which cyclopentene shields the amide bond. Notably, cyclopentene as a bioisostere of proline is an appealing scaffold in medicinal chemistry. An extensive combined experimental and computational study provided more profound insight into the supramolecular landscape of <b>1</b> with respect to similar derivatives deposited in the CSD, including the tendency of cyclopentene for the generation of pseudo-cyclic motifs through weak H-bonding and π-based intramolecular interactions. These weak interactions have been examined by either the quantum theory of 'atoms-in-molecules' (QTAIM) or complex Hirshfeld surface methodology, including enrichment ratios, molecular electrostatic potential surfaces and energy frameworks. In all analysed crystals, all types of H-bonded motifs involving cyclopentene are formed at all levels of supramolecular architecture. A library of cyclopentene-based H-bonding synthons is provided. A molecular docking study depicted vital interactions of cyclopentene with key amino acid residues inside the active sites of two prominent protein kinases, uncovering the therapeutic potential of <b>1</b> against breast cancer. To a large extent, dispersion forces have significance in stabilizing the supramolecular structure of both ligand and bio-complex ligand-protein. Finally, the satisfactory <i>in silico</i> bio-pharmacokinetic profile of <b>1</b> related to drug-likeness and blood-brain barrier permeation was also revealed.