Published online Jun 16, 2023. doi: 10.5497/wjp.v12.i3.25
Peer-review started: March 1, 2023
First decision: April 13, 2023
Revised: May 5, 2023
Accepted: May 31, 2023
Article in press: May 31, 2023
Published online: June 16, 2023
Some isopavines can exhibit important biological activity in the treatment of neurological disorders since it is considered an antagonist of the specific N-methyl-D-Aspartate (NMDA) receptor. Amurensinine is an isopavine which still has few studies. In view of the potential of isopavines as NMDA receptor antagonists, theoretical studies using bioinformatics were carried out in order to investigate whether Amurensinine binds to the NMDA receptor and to analyze the receptor/Ligand complex. This data can contribute to understanding of the onset of neurological diseases and contribute to the planning of drugs for the treatment of neurological diseases involving the NMDA receptor.
To investigate the interaction of the antagonist Amurensinine on the GluN1A/ GluN2B isoform of the NMDA receptor using bioinformatics.
The three-dimen-sional structure of the GluN1A/GluN2B NMDA receptor was selected from the Protein Data Bank (PDB) - PDB: 4PE5, and the three-dimen-sional structure of Amurensinine (ligand) was designed and optimized using ACD/SchemsketchTM software. Prediction of the protonation state of Amur-ensinine at physiological pH was performed using MarvinSketch software (ChemAxon). Protonated and non-protonated Amurensin were prepared using AutoDock Tools 4 software and simulations were performed using Autodock Vina v.1.2.0. The receptor/Ligand complexes were analyzed using PyMol (Schrödinger, Inc) and BIOVIA Discovery Studio (Dassault Systemes) software. To evaluate the NMDA receptor/Amurensinine complex and validate the molecular docking, simulations using NMDA receptor and Ifenprodil antagonist were performed under the same conditions. Ifenprodil was also designed, optimized and protonated, under the same conditions as Amurensinine.
Molecular docking simulations showed that both non-protonated and protonated Amurensinine bind to the amino terminal domain (ATD) domain of the GluN1A/GluN2B NMDA receptor with significant affinity energy, -7.9 Kcal/mol and -8.1 Kcal/mol, respectively. The NMDA receptor/non-protonated Amurensinine complex was stabilized by 15 bonds, while the NMDA receptor/protonated Amurensinine complex was stabilized by less than half, 6 bonds. Despite the difference in the number of bonds, the variation in bond length and the average bond length values are similar in both complexes. The complex formed by the NMDA receptor and Ifenprodil showed an affinity energy of -8.2 Kcal/mol, a value very close to that obtained for the NMDA receptor/Amurensinine complex. Molecular docking between Ifenprodil and the GluN1A /GluN2B NMDA receptor demonstrated that this antagonist interacts with the ATD of the receptor, which validates the simulations performed with Amurensinine.
Amurensinine binds to the NMDA receptor on ATD, similar to Ifenprodil, and the affinity energy is closer. These data suggest that Amurensinine could behave as a receptor inhibitor, indicating that this compound may have a potential biological application, which should be evaluated by in vitro and preclinical assays.
Core Tip: Amurensinine binds to a region of the amino terminal domain on the N-methyl-D-Aspartate receptor and the interaction is stabilized mainly by covalent bonds, which confer an affinity energy of significant value to the receptor/Ligand complex. The interaction between Amurensinine and the receptor, which is involved in neurological diseases, suggests that this isopavine may interfere with its function, so it may have therapeutic potential in this area.