The structure of bioactive compounds inside their biological target is mainly dictated by the intermolecular interactions present in the binding side, whereas intramolecular interactions are responsible for the structure of an isolated molecule. Accordingly, this work reports the relative significance of these interactions for the bioactive conformation of the N-protonated epinephrine. The crystallized structure of epinephrine has a gauche orientation of the O-C-C-N torsion angle. Conformational analysis in the gas phase and implicit water was performed to investigate the main intramolecular forces favoring this conformational preference, which was primarily attributed to the electrostatic interaction between hydroxyl and ammonium groups. However, when the conformers were docked into the active site, intramolecular interactions were surpassed by intermolecular hydrogen bonds with neighboring amino acid residues. Nonetheless, structural modifications aiming at strengthening intramolecular interactions could be used to modulate a bioactive conformation, thereby assisting in the structure-based design of new chemical entities.
Keywords: Conformation analysis; electrostatic gauche effect; hyperconjugation; intermolecular interactions; intramolecular hydrogen bond.
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