3 research outputs found
Possible binding sites and interactions of propanidid and AZD3043 within the γ-aminobutyric acid type A receptor (GABA<sub>A</sub>R)
<p>Propanidid is an intravenous anesthetic with transient action and rapid recovery features, but it is clinically unacceptable due to its side effects. AZD-3043, an analog of propanidid with the methoxy group substituted by the ethoxy group, has become the focus of recent development efforts. Although propanidid and AZD-3043 are known to act by potentiating the γ-aminobutyric acid type A receptors (GABA<sub>A</sub>Rs), their action sites and binding modes in the recognition of target proteins still remain unclear. In this study, molecular docking and ONIOM calculations were performed to explore the possible binding sites and binding modes of propanidid and AZD-3043 with the GABA<sub>A</sub>R. The predicted active region located in the transmembrane domain (TMD) of GABA<sub>A</sub>R was identified as the most favorable binding site for propanidid and AZD-3043, with the highest docking score (−39.69 and −39.44 kcal/mol, respectively) and the largest binding energy (−88.478 and −78.439 kcal/mol, respectively). The important role of amino acids Asp245, Asp424, Asp425, Arg428, Phe307, and Ser308 in determining the binding modes of propanidid or AZD-3043 with GABA<sub>A</sub>R was revealed. The detailed molecular interactions between propanidid and AZD-3043 and the GABA<sub>A</sub>R were revealed for the first time. This could improve our understanding of the action mechanism of general anesthetics and will be helpful for the design of more potential lead-like molecules.</p
β‑Galactosidase-Activated and Red Light-Induced RNA Modification Strategy for Prolonged NIR Fluorescence/PET Bimodality Imaging
Improving
the retention of small-molecule-based therapeutic agents
in tumors is crucial to achieve precise diagnosis and effective therapy
of cancer. Herein, we propose a β-galactosidase (β-Gal)-activated
and red light-induced RNA modification (GALIRM) strategy for prolonged
tumor imaging. A β-Gal-activatable near-infrared (NIR) fluorescence
(FL) and positron emission tomography (PET) bimodal probe 68Ga-NOTA-FCG consists of a triaaza triacetic acid chelator NOTA for 68Ga-labeling, a β-Gal-activated photosensitizer CyGal,
and a singlet oxygen (1O2)-susceptible furan
group for RNA modification. Studies have demonstrated that the probe
emits an activated NIR FL signal upon cleavage by endogenous β-Gal
overexpressed in the lysosomes, which is combined with the PET imaging
signal of 68Ga allowing for highly sensitive imaging of
ovarian cancer. Moreover, the capability of 68Ga-NOTA-FCG
generating 1O2 under 690 nm illumination could
be simultaneously unlocked, which can trigger the covalent cross-linking
between furan and nucleotides of cytoplasmic RNAs. The formation of
the probe-RNA conjugate can effectively prevent exocytosis and prolong
retention of the probe in tumors. We thus believe that this GALIRM
strategy may provide entirely new insights into long-term tumor imaging
and efficient tumor treatment
The Role of the Hydroxyl Group in Propofol–Protein Target Recognition: Insights from ONIOM Studies
Propofol
(PFL, 1-hydroxyl-2,6-diisopropylbenzene) is currently
used widely as one of the most well-known intravenous anesthetics
to relieve surgical suffering, but its mechanism of action is not
yet clear. Previous experimental studies have demonstrated that the
hydroxyl group of PFL plays a dominant role in the molecular recognition
of PFL with receptors that lead to hypnosis. To further explore the
mechanism of anesthesia induced by PFL in the present work, the exact
binding features and interaction details of PFL with three important
proteins, human serum albumin (HSA), the pH-gated ion channel from <i>Gloeobacter violaceus</i> (GLIC), and horse spleen apoferritin
(HSAF), were investigated systematically by using a rigorous three-layer
ONIOM (M06-2X/6-31+G*:PM6:AMBER) method. Additionally, to further
characterize the possible importance of such hydroxyl interactions,
a similar set of calculations was carried out on the anesthetically
inactive fropofol (FFL, 1-fluoro-2,6-diisopropylbenzene) in which
the fluorine was substituted for the hydroxyl. According to the ONIOM
calculations, atoms in molecules (AIM) analyses, and electrostatic
potential (ESP) analyses, the significance of hydrogen bond, halogen
bond, and hydrophobic interactions in promoting proper molecular recognition
was revealed. The binding interaction energies of PFL with different
proteins were generally larger than FFL and are a significant determinant
of their differential anesthetic efficacies. Interestingly, although
the hydrogen-bonding effect of the hydroxyl moiety was prominent in
propofol, the substitution of the 1-hydroxyl by a fluorine atom did
not prevent FFL from binding to the protein via a halogen-bonding
interaction. It therefore became clear that multiple specific interactions
rather than just hydrogen or halogen bonds must be taken into account
to explain the different anesthesia endpoints caused by PFL and FFL.
The contributions of key residues in ligand–receptor binding
were also quantified, and the calculated results agreed with many
available experimental observations. This work will provide complementary
insights into the molecular mechanisms of anesthetic action for PFL
from a robust theoretical point of view. This will not only assist
in interpreting experimental observations but will also help to develop
working hypotheses for further experiments and future drug design