Intramolecular interactions contributing for the conformational preference of bioactive diphenhydramine: Manifestation of the gauche effect

Rezende, Fátima M.P. de; Andrade, Laize A. F.; Freitas, Matheus P.

doi:10.1016/j.molstruc.2015.03.033

Cited by 6 publications

(1 citation statement)

References 30 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Usually, intermolecular ligand−enzyme interactions overcome intramolecular interactions in the substrate as driving forces of the conformational equilibrium in a biological environment. For example, while the gauche effect caused by intramolecular interactions, namely, hyperconjugation and electrostatic effects, can rule the bioactive conformation of diphenhydramine, 8 the most stable geometry for the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in the gas phase and solution does not match its bioactive conformation complexed with the active site of TIR1 ubiquitin ligase enzyme. 9 Thus, this study aims to analyze the intramolecular interactions governing the conformational stability of enflurane and, subsequently, examine their roles in the possible bioactive conformation of enflurane in the Integrin LFA-1 enzyme, predicted using docking studies.…”

Section: ■ Introductionmentioning

confidence: 99%

Conformational Exploration of Enflurane in Solution and in a Biological Environment

et al. 2015

Self Cite

View full text Add to dashboard Cite

Enflurane is a fluorinated volatile anesthetic, whose bioactive conformation is not known. Actually, a few studies have reported on the conformations of enflurane in nonpolar solution and gas phase. The present computational and spectroscopic (infrared and NMR) work shows that three pairs of isoenergetic conformers take place in the gas phase, neat liquid, polar, and nonpolar solutions. According to docking studies, a single conformation is largely preferred over its isoenergetic isomers to complex with the active site of Integrin LFA-1 enzyme (PDB code: 3F78 ), where the widely used anesthetic isoflurane (a constitutional isomer of enflurane) is known to bind. Weak hydrogen bonding from an electrostatic interaction between the CHF2 hydrogen and the central CF2 fluorines was not found to rule the conformational isomerism of enflurane. Moreover, intramolecular interactions based on steric, electrostatic, and hyperconjugative effects usually invoked to describe the anomeric effect are not responsible for the possible bioactive conformation of enflurane, which is rather governed by the enzyme induced fit.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Conformational Exploration of Enflurane in Solution and in a Biological Environment

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

Theoretical Study on the Conformational Bioeffect of the Fluorination of Acetylcholine

Silla

Silva

Freitas

2017

Molecular Informatics

View full text Add to dashboard Cite

There has been an increasing interest in the study of fluorinated derivatives of gamma-aminobutyric acid (GABA), an acetylcholine (AC) analog. This work reports a theoretical study on the effect of an α-carbonyl fluorination in AC, aiming at understanding the role of a distant fluorine relative to the positively charged nitrogen on the conformational folding of the resulting fluorinated AC. In addition, the chemical and structural changes were evaluated on the basis of ligand-enzyme (acetylcholinesterase) interactions. In an enzyme-free environment, the fluorination yields conformational changes relative to AC due to the appearance of some attractive interactions with fluorine and a weaker steric repulsion between the fluorine substituent and the carboxyl group, rather than to a possible electrostatic interaction F⋅⋅⋅N . Moreover, the gauche orientation in the N-C-C-O fragment of AC owing to the electrostatic gauche effect is reinforced after fluorination. For instance, the conformational equilibrium in AC is described by a competition between gauche and anti conformers (accounting for the N-C-C-O dihedral angle) in DMSO, while the population for a gauche conformer in the fluorinated AC is almost 100 % in both gas phase and DMSO. However, this arrangement is disrupted in the biological environment even in the fluorinated derivative (whose bioconformation-like geometry shows a ligand-protein interaction of -84.1 kcal mol against -79.5 kcal mol for the most stable enzyme-free conformation), which shows an anti N-C-C-O orientation, because the enzyme induced-fit takes place. Nevertheless, the most likely bioconformation for the fluorinated AC does not match the bioactive AC backbone nor the most stable enzyme-free conformation, thus revealing the role of fluorination on the bioconformational control of AC.

show abstract

The Role of Intramolecular Interactions on the Bioactive Conformation of Epinephrine

Silva

Silla

Santos

et al. 2019

Molecular Informatics

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Intramolecular interactions contributing for the conformational preference of bioactive diphenhydramine: Manifestation of the gauche effect

Cited by 6 publications

References 30 publications

Conformational Exploration of Enflurane in Solution and in a Biological Environment

Conformational Exploration of Enflurane in Solution and in a Biological Environment

Theoretical Study on the Conformational Bioeffect of the Fluorination of Acetylcholine

The Role of Intramolecular Interactions on the Bioactive Conformation of Epinephrine

Contact Info

Product

Resources

About