Ebola is a deadly virus that has recently emerged as an enormous public health concern which causes dangerous illness with high fatality rates of 90%. Potential treatments for the disease are currently being studied although no specific treatment or vaccine exists and hence the need to identify novel inhibitors to aid combat the disease. The VP24 protein of the Ebola virus (EBOV) is believed to play a very key role in the pathology and replication of the Ebola virus disease. VP24 is also known to interfere with the human system’s response to viral infections, thus making it a viable target for combating Ebola Virus disease. This study therefore seeks to identify potential lead compounds from the African flora that can inhibit the activity of the Ebola virus VP24 protein by computer-aided virtual screening. Molecules from AfroDB were used for docking studies with the protein target. Drugs that have shown to inhibit the activity VP24 protein were also docked and their binding energy were examined and compared to those obtained from AfroDB. 21 compounds passed as potent VP24-inhibiting lead compounds. The docking results showed that AfroDB ligand ZINC95486070 demonstrated high binding properties with VP24 than all the VP24-inhibitor drugs (binding energy -9.7 kcal/mol) based on the molecular docking simulation. The leads from AfroDB generally demonstrated better binding potential than the VP24-inhibitor compounds in the computational studies. ****
Ebola virus disease (EVD) is a viral hemorrhagic fever which affects humans and other primates, and is caused by ebolaviruses. Similar to other filoviruses, Ebola virus (EBOV) replicates very efficiently in many cells, giving rise an appreciable number of virus in cells of the mononuclear phagocyte system (MPS) and other cells including liver cells, fibroblasts, and adrenal gland cells. EBOV is believed to be transmitted to humans through direct contact with blood, mucous membranes or through skin contact. The disease is associated with a high risk of death, killing an average of about 50 percent of those infected with the highest death rate being around 90 percent.
The World Health Organization reported a total of 24 Ebola outbreaks involving 1,716 cases from 1976 to 2013. The largest outbreak ever recorded was the epidemic in West Africa mostly in Liberia, Sierra Leone and Guinea, claiming about 11,000 lives out of about 28,000 cases which occurred from December 2013 to January 2016 and the most recent outbreak occurring in May 2017 in the Democratic Republic of the Congo.
EBOV is a single-stranded RNA virus which encodes seven proteins: nucleoproteins (NP), glycoprotein (GP), polymerase (L), VP24, VP30, VP35, and VP40. VP24 is a secondary matrix protein that plays a very key role in the pathology of the Ebola virus disease. The VP24 and VP35 structural proteins of EBOV are believed to play a very important role in interfering with the human immune system’s response to viral infections.
VP24 disrupts the signalling pathway of STAT1. VP24 inhibits the function of karyopherins (KPNA) by binding to it in a region which overlaps with the region where STAT1 binds to the KPNA due to the higher binding affinity between the VP24-KPNA complex. As a result, STAT1 is not able to elicit an immune response and is able to transport viral components into the nucleus or the target cell. VP24 is also responsible for forming fully functional and infectious virus-like particles (VLPs), the promotion of viral nucleocapsid formation and the regulation of the replication. The broad roles the VP24 protein in the replication of the virus and immune-suppression makes it a viable target for combating Ebola Virus disease.
Potential treatments for the disease are currently being studied although no specific treatment or vaccine exists. Few currently available drugs including Miglustat, Ouabain, Nilotinib, Clomiphene, Toremifene among others have shown to be possible VP24-inhibitors. Ouabain, Nilotinib and Miglustat are responsible for blocking viral replication. BCX4430 (Immucillin-A), an antiviral drug, has also been developed as a potential treatment for deadly filovirus infections such as Ebola virus disease and Marburg virus disease
Computer-aided drug design (CADD) has evolved to become one of the most progressive and effective research fields, which also uses cost-efficient and reliable techniques to identify and discover lead compounds for many diseases. Many drugs for combating different diseases on the market are either produced from natural compounds or derived from natural sources. The African flora remains an untapped reservoir of new drug candidates for combating various kinds of diseases. The African continent can boast of its wealth in biodiversity, which can be exploited to produce novel drug candidates from its natural sources.
This study therefore seeks to discover potential drug candidates from African natural compounds for combating Ebola virus disease by inhibiting the VP24 protein through in silico drug design method, and comparing their interactions with the protein to other VP24-inhibitor drugs.
This study has deployed some software such as GROMACS, UCSF Chimera 1.12, Pymol, Pyrx and Marvin from ChemAxon.
Obtaining VP24 Protein, African Natural Compounds and VP24-Inhibitor Drugs
In this study, the 3D structure of the VP24 protein was retrieved from RCSB PDB website (http://www.rcsb.org/pdb/home/home.do) with corresponding PDB ID: 4M0Q. The African natural compounds were also obtained from AfroDB, a database containing naturally occurring African compounds 1. A total of 833 compounds were obtained from AfroDB. Drugs from previous works that have shown to inhibit the activities of the VP24 protein (Miglustat, Ouabain, Nilotinib, Clomiphene, Toremifene and BCX4430) were retrieved from PubChem (https://pubchem.ncbi.nlm.nih.gov/).
ADMET Screening of AfroDB Compounds
Admet Predictor 8.0 by Simulations Plus, Inc. was used to screen the 833 AfroDB compounds in order to eliminate any unwanted ligands that have high toxicity and very high (>350gmol-1) or very low (