In Search of Ebola Virus Glycoprotein Inhibitors: A Structure-Based Drug Design Study
Hassan, Nazia (2021-03-05)
In Search of Ebola Virus Glycoprotein Inhibitors: A Structure-Based Drug Design Study
(05.03.2021)
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
suljettu
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021050428726
https://urn.fi/URN:NBN:fi-fe2021050428726
Tiivistelmä
Ebola virus (EBOV) is one of the deadliest viruses that causes haemorrhagic fever in humans and the fatality rate is more than 50%. The biggest outbreak of Ebola virus disease (EVD) occurred in 2014-2016 in West Africa causing more than 11,000 deaths. The most recent outbreak of EVD has begun on the 7th of February 2021 in Democratic Republic of Congo (DRC).
EBOV contains a single protein, the glycoprotein, on its outer membrane. The Ebola virus glycoprotein (EBOV GP) mediates the attachment to the host cell, membrane fusion and endosomal entry of the virus and thereby EBOV GP is considered as a potential drug target.
To date, there are only a few vaccines and one monoclonal antibody drug that have been approved by the authorities to treat EVD. However, as of now, no small molecule drugs have been approved against EVD. In the year 2019, World Health Organization (WHO) has prequalified a vaccine called Ervebo to prevent EBOV infection. Moreover, a number of scientific studies have shown that several FDA-approved drugs bind in the same inner cavity of EBOV GP and thus, interfere with as well as destabilize EBOV GP by reducing its thermal stability.
In this study, pharmacophore models have been developed based on the known EBOV GP binding compounds and the detailed analysis of their binding site interactions derived from the available crystal structures. The pharmacophore models were used to screen a natural compound database in order to find novel, potent small-molecular inhibitors with improved specificity for EBOV GP. The most promising virtual hits obtained in this work will be biologically tested via collaboration.
In this study, the molecular visualization software PyMOL was used for the initial structural analysis of the crystallized protein-ligand complexes. Molecular modelling suite Maestro’s GLIDE tool was used for docking, Prime/MMGBSA module for estimating binding energies of ligand-protein complexes, and the PHASE tool for creating pharmacophore models and screening through the MolPort natural compound library.
EBOV contains a single protein, the glycoprotein, on its outer membrane. The Ebola virus glycoprotein (EBOV GP) mediates the attachment to the host cell, membrane fusion and endosomal entry of the virus and thereby EBOV GP is considered as a potential drug target.
To date, there are only a few vaccines and one monoclonal antibody drug that have been approved by the authorities to treat EVD. However, as of now, no small molecule drugs have been approved against EVD. In the year 2019, World Health Organization (WHO) has prequalified a vaccine called Ervebo to prevent EBOV infection. Moreover, a number of scientific studies have shown that several FDA-approved drugs bind in the same inner cavity of EBOV GP and thus, interfere with as well as destabilize EBOV GP by reducing its thermal stability.
In this study, pharmacophore models have been developed based on the known EBOV GP binding compounds and the detailed analysis of their binding site interactions derived from the available crystal structures. The pharmacophore models were used to screen a natural compound database in order to find novel, potent small-molecular inhibitors with improved specificity for EBOV GP. The most promising virtual hits obtained in this work will be biologically tested via collaboration.
In this study, the molecular visualization software PyMOL was used for the initial structural analysis of the crystallized protein-ligand complexes. Molecular modelling suite Maestro’s GLIDE tool was used for docking, Prime/MMGBSA module for estimating binding energies of ligand-protein complexes, and the PHASE tool for creating pharmacophore models and screening through the MolPort natural compound library.