Finding potential inhibitors against RNA-dependent RNA polymerase (RdRp) of bovine ephemeral fever virus (BEFV): an in-silico study

Abstract

The bovine ephemeral fever virus (BEFV) is an enzootic agent that affects millions of bovines and causes major economic losses. Though the virus is seasonally reported with a very high morbidity rate (80–100%) from African, Australian, and Asiatic continents, it remains a neglected pathogen in many of its endemic areas, with no proper therapeutic drugs or vaccines presently available for treatment. The RNA-dependent RNA polymerase (RdRp) catalyzes the viral RNA synthesis and is an appropriate candidate for antiviral drug developments. We utilized integrated computational tools to build the 3D model of BEFV-RdRp and then predicted its probable active binding sites. The virtual screening and optimization against these active sites, using several small-molecule inhibitors from a different category of Life Chemical database and FDA-approved drugs from the ZINC database, was performed. We found nine molecules that have docking scores varying between −6.84 to −10.43 kcal/mol. Furthermore, these complexes were analyzed for their conformational dynamics and thermodynamic stability using molecular dynamics simulations in conjunction with the molecular mechanics generalized Born surface area (MM-GBSA) scheme. The binding free energy calculations depict that the electrostatic interactions play a dominant role in the RdRp-inhibitor binding. The hot spot residues, such as Arg565, Asp631, Glu633, Asp740, and Glu707, were found to control the RdRp-inhibitor interaction. The ADMET analysis strongly suggests favorable pharmacokinetics of these compounds that may prove useful for treating the BEFV ailment. Overall, we anticipate that these findings would help explore and develop a wide range of anti-BEFV therapy.

Communicated by Ramaswamy H. Sarma

Keywords:

• Bovine ephemeral fever virus (BEFV)
• RNA-dependent RNA polymerase (RdRp)
• virtual screening
• molecular dynamics
• MMGBSA

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The data that support the findings of this study are available from the corresponding author (PK) upon reasonable request.

Authors contributions

PK and DN conceived and supervised the project. SP and NAJ conducted molecular dynamic simulations, performed data analysis, and wrote the manuscript. MFS performed data analysis and took part in manuscript writing. PK and DN edited the manuscript. All authors have approved the final version of the manuscript.

Ethics statement

There is no human or animal experiment in this study.

Additional information

Funding

This work was partially supported by the Department of Biotechnology, Govt. of India (grant number BT/RLF/Re-entry/40/2014, Ramalingaswami Re-entry Fellowship), and Science and Engineering Research Board, Govt. of India (grant number: ECR/2016/000130). SP is supported by University Grant Commission (UGC, India) fellowship for her doctoral studies.