Computational characterization of the glutamate receptor antagonist perampanel and its close analogs: density functional exploration of conformational space and molecular docking study

Abdul Akim D. Guseynov, Sergey A. Pisarev, Dmitry A. Shulga, Vladimir A. Palyulin, Maxim V. Fedorov, Dmitry S. Karlov

    Research output: Contribution to journalArticlepeer-review

    4 Citations (Scopus)

    Abstract

    Perampanel approved by FDA in 2012 is a first-in-class antiepileptic drug which inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents. It is markedly more active than many of its close analogs, and the reasons for this activity difference are not quite clear. Recent crystallographic studies allowed the authors to identify the location of its binding site. Unfortunately, the resolution is low, and the detailed description of perampanel binding mode is still in part speculative. Here we provide a detailed DFT-level conformational analysis of perampanel in a vacuum and in the solvents, mimicking the protein environment, followed by quantum theory of atoms in molecules (QTAIM), non-covalent interactions (NCI), and natural bond orbital (NBO) analyses. The findings indicate the electrostatic nature of the intramolecular interactions which contribute to energy differences of the conformations in a vacuum whereas the increase of dielectric constant leads to the energy equalization of conformations. Based on these results, the docking study was performed to investigate possible binding modes of perampanel and its close analogs in AMPA receptors. The influence of the pyridine nitrogen and cyano group position was explained based on the results of conformational analysis and molecular docking. These findings may contribute to the design of novel antiepileptic drugs and the development of novel approaches to treat neurodegenerative diseases and major depressive disorder.

    Original languageEnglish
    Article number312
    JournalJournal of Molecular Modeling
    Volume25
    Issue number10
    DOIs
    Publication statusPublished - 1 Oct 2019

    Keywords

    • Allosteric antagonist
    • Conformational analysis
    • Density functional theory calculations
    • Docking
    • Glutamate receptors

    Fingerprint

    Dive into the research topics of 'Computational characterization of the glutamate receptor antagonist perampanel and its close analogs: density functional exploration of conformational space and molecular docking study'. Together they form a unique fingerprint.

    Cite this