Department of Chemistry, Federal University of Lavras, 37200-000, Lavras, MG, Brazil.
Mol Inform. 2019 Jun;38(6):e1800167. doi: 10.1002/minf.201800167. Epub 2019 Apr 4.
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.
生物活性化合物在其生物靶标内的结构主要由结合部位存在的分子间相互作用决定，而分子内相互作用则负责孤立分子的结构。因此，这项工作报告了这些相互作用对于 N-质子化肾上腺素的生物活性构象的相对重要性。肾上腺素的结晶结构具有 O-C-C-N 扭转角的gauche 取向。在气相和隐式水中进行构象分析，以研究有利于这种构象偏好的主要分子内力，这主要归因于羟基和铵基团之间的静电相互作用。然而，当构象体被对接入活性部位时，分子内相互作用被与相邻氨基酸残基的分子间氢键所超越。尽管如此，旨在增强分子内相互作用的结构修饰可用于调节生物活性构象，从而有助于基于结构的新化学实体的设计。
