Potential Ebola drug targets — filling the gap: a critical step forward towards the design and discovery of potential drugs

Abstract

Among the classified neglected infectious diseases, the Ebola virus (EboV) remains a challenging epidemic. This deadly virus has been reported as a category A bioweapon organism by the World Health Organization due to the serious threat it poses. To date, Ebola drug discovery proves challenging. Proteins need to be targeted at the relevant biologically active site for drug or inhibitor binding to be effective. Due to insufficient experimental data to confirm the biologically active binding site for novel protein targets, researchers often rely on computational prediction methods to identify binding sites. Many computational studies have attempted to identify the biological active site for EboV proteins, however, the methods employed are not sufficiently validated. This has prompted us to provide a comprehensive molecular understanding of the various targets of the EboV, including three-dimensional structures, active site identification and further validation. Herein we report the account of a three-dimensional homology model of the unresolved EboV RNA-dependent RNA polymerase (RdRp), as well as a comprehensive analysis of the binding site residues of all proteins of the EboV. Docking-aided active site determination was carried out to identify possible active sites on the homology model of RdRp. Binding free energy calculations revealed subtle differences in the binding at each site. These results can also provide some potential clues for further design of novel inhibitors to treat this killer virus and is a critical cornerstone of research into the EboV.

Bioinformatics Approach to Screening and Developing Drug against Ebola

“…It encodes seven structural protein, namely, nucleoprotein (NP), glycoprotein (GP), RNA-dependent RNA polymerase (L), matrix protein (VP40), and three nucleocapsid proteins (VP24, VP30, and VP35) [15,16]. It also encodes one nonstructural protein, the secretory glycoprotein (sGP) [17].…”

“…The seven structural proteins and one nonstructural protein have an imperative role in Ebola virus life cycle [16]. NP: viral replication and scaffold for additional viral proteins.…”

“…VP30: viral transcription activator. VP35: multi-virulence functionality, innate immune antagonist, and an RNAi silencing suppressor [16,17].…”

“…The negligence occurs to all tropical diseases by only 13 out of 1393 new approved drugs between 1975 and 1999 that were indicated for tropical disease [30]. However, the frequent outbreaks in the last decade and the massive outbreak which was occurred in 2014 have drawn much attention to drug development for Ebola [16]. Without available treatment or vaccine, paramedic only relied on palliative care for the infected patients and barrier methods to prevent the transmission [31].…”

“…In addition, the active site residues of each protein have also been identified, except for NP. L is the only Ebola virus protein with unavailable 3D structure and unidentified active site [16]. Thus, researchers use a bioinformatics approach to utilize the readily available genomic and proteomic data to research drug design and discovery.…”