Molecular docking enabled updated screening of the matrix protein VP40 from Ebola virus with millions of compounds in the MCULE database for potential inhibitors.

Hasanain Abdulhameed Odhar

doi:10.6026/97320630015627

Abstract

Ebola virus is known for several outbreaks of hemorrhagic fever in West Africa. This RNA virus is linked to high fatality and easy transmission. Recently, an effective vaccine and a monoclonal antibody cocktail have been introduced to combat Ebola virus infection. The matrix protein VP40 of Ebola virus is a known drug target and it is essential for viral life cycle through participation in RNA transcription as well as for the budding of the mature virus. It is known that residues phenylalanine 125 and arginine 134 of VP40 are involved in the interaction with RNA. Therefore, it is of interest to screen VP40 with millions of compounds at the mcule.com database for potential inhibitors. The output hits were ranked according to their minimum binding energy to matrix protein VP40. We further calculated the pharmacokinetics and toxicology properties for the best five hits using several predictive ADME analysis web tools. We report a candidate lead (compound #5: ((10R)-10-(4-hydroxyphenyl)-11,12,14,16-tetraazatetracyclo[7.7.0.02,7.011,15] hexadeca-1(16), 2(7),3,5,8,12,14-heptaen-8-ol)) with high drug-likeness score, promising lead-likeness behaviour and high median lethal dose. The candidate lead compound #5 engages in hydrogen bonding and hydrophobic interactions with VP40 active site residues. Thus, the lead compound #5 is recommended for further in vitro and in vivo validations for further consideration.

Highlights

The Ebola virus (EboV) is an antisense RNA virus that had been responsible for several outbreaks of hemorrhagic fever mainly in West Africa
The chemical structures and characteristics for the top five hits as screened virtually against Ebola virus VP40 protein are shown in Figure 2 and Table 1 respectively
It is engaged in Pi hydrophobic interaction and van der Waals bonding with Phenylalanine 125 and Arginine 134 respectively

Summary

Introduction

The Ebola virus (EboV) is an antisense RNA virus that had been responsible for several outbreaks of hemorrhagic fever mainly in West Africa. This virus has been categorized as a bio-weapon hazard due to its high transmission capacity with fatality rate of about 90% [1, 2]. Computational approaches are currently employed to generate novel anti-EboV compounds. The RNA genome of Ebola virus is composed of about 19 Kb nucleotides that encodes for seven structural proteins These conserved proteins include glycoprotein (GP), matrix protein VP40, VP35, VP30, VP24, nucleoprotein (NP) and polymerase L protein. These proteins can serve as potential drug targets for high throughput screening (HTS) [1, 6]

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