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Identification of potential inhibitor against Ebola virus VP35: insight into virtual screening, pharmacoinformatics profiling, and molecular dynamic studies

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Abstract

The Ebola virus is a deadly pathogen that causes a highly lethal hemorrhagic fever illness in humans, sometimes known as Ebola virus sickness (EVD). The Ebola virus polymerase cofactor VP35 acts by preventing the establishment of a cellular antiviral state by blocking virus-induced phosphorylation and activation of interferon regulatory factor 3 (IRF3), a transcription factor required for the induction of interferons alpha and beta, thus making it an appealing therapeutic target because there are currently not many available and effective therapeutic agents available against this virus. This study presented a molecular docking–based virtual screening (VS) of 10,829 compounds acquired from multiple databases against the VP35 receptor using Auto Dock Vina software to discover potential inhibitors. According to the results of the screening, the top two drugs, irinotecan and fexofenadine, exhibited a high affinity for the VP35 binding region. Their binding affinities were −8.2 and −8.0 kJ/mol, indicating that they were tightly bound to the target receptor. These results outperformed those obtained with the co-crystallized ligand, which exhibited a binding affinity of −6.8 kJ/mol. As a result of the VS and molecular docking techniques, novel VP35 inhibitors from diverse databases were discovered using the Lipinski rule of five and functional molecular interactions with the target protein, as proven by the findings of this work. The findings suggest that the compounds discovered may offer viable avenues for the development of Ebola virus VP35 inhibitors and that they need further evaluation and investigation.

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Acknowledgements

The authors would like to acknowledge the Bioinformatics lab facility of the School of Interdisciplinary Studies, Jamia Hamdard University New Delhi, 110062, India, during the work. The help from Dr. Mymoona Akhter, Bioinformatics lab, is also of great importance, particularly during the MD simulation analysis. We also thank BioNome that arranged the Desmond Schrodinger part in the manuscript for simulation studies.

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Author notes

  1. Ratul Bhowmik and Ajay Manaithiya contributed equally

Authors and Affiliations

  1. Medicinal Chemistry and Molecular Modelling Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India

    Ratul Bhowmik, Ajay Manaithiya, Sara Rehman & Shubham Roy

  2. School of Interdisciplinary Studies, Jamia Hamdard, New Delhi, 110062, India

    Bharti Vyas

  3. Department of Pharmaceutics, Kolkata-Group of Institutions, NSHM Knowledge Campus, Kolkata, 700053, West Bengal, India

    Ranajit Nath

  4. Department of Pharmacology, Kolkata-Group of Institutions, NSHM Knowledge Campus, Kolkata, 700053, West Bengal, India

    Ratna Roy

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  1. Ratul Bhowmik
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Contributions

Ratul Bhowmik conducted database searches, compiled references, evaluated data, and wrote the article; Ajay Manaithiya contributed significantly to the design, analysis, manuscript preparation, revision, and writing—original draft; Bharti Vyas contributed to the conception of the study and formal analysis; Ranajit Nath helped to organize the literature; Sara Rehman contributed to the collection of data and checked the chemical structures; Shubham Roy polished the language; Ratna Roy contributed to the table and picture layout. All authors contributed to the paper. All authors read and approved the final manuscript. They warrant that the article is the authors’ original work, has not received prior publication, and is not under consideration for publication elsewhere.

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Correspondence to Ajay Manaithiya.

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Highlights

• A structural library including 10829 ligands was evaluated via molecular docking against the Ebola virus VP35.

• Fexofenadine and irinotecan have a high affinity for Ebola virus VP35 when used as a protein-ligand complex.

• IMODs and Desmond were used to determine the flexibility and disordered areas of proteins.

• Selected compounds have been shown to inhibit the Ebola virus VP35.

• Virtual high-throughput screening and pharmacoinformatics aid in the development of new drugs.

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Bhowmik, R., Manaithiya, A., Vyas, B. et al. Identification of potential inhibitor against Ebola virus VP35: insight into virtual screening, pharmacoinformatics profiling, and molecular dynamic studies. Struct Chem 33, 815–831 (2022). https://doi.org/10.1007/s11224-022-01899-y

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  • DOI: https://doi.org/10.1007/s11224-022-01899-y

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