Discovery of Indonesian natural products as potential inhibitor of Ebola virus VP40 through molecular docking simulation

Nasution, Mochammad Arfin Fardiansyah; Alkaff, Ahmad Husein; Tambunan, Usman Sumo Friend

doi:10.1063/1.5064052

Cited by 4 publications

(4 citation statements)

References 38 publications

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“…The binding site residues consisted of Leu6, Pro7, Pro10, Met14, Ala27, Arg28, Asn31, Ser32, Asn33, Gly99, Val100, Ala101, Asp102, Lys104, Thr105, Asp144, His145, Pro146, Leu147, Arg148, Arg151, Trp191, Thr192, and Asp193. This binding site is consistent with that predicted previously using Site Finder [ 48 ]. The study also suggested that there is a higher likelihood for a small molecule to bind in this region [ 48 ].…”

Section: Resultssupporting

confidence: 92%

“…This binding site is consistent with that predicted previously using Site Finder [ 48 ]. The study also suggested that there is a higher likelihood for a small molecule to bind in this region [ 48 ].…”

Section: Resultssupporting

confidence: 92%

“…The in silico characterization of the potential lead compounds using ADMET testing corroborated their drug-like properties. It was observed that most of the compounds bind in the loop region rather than the RNA binding site as suggested previously [ 48 ]. The biological activities of the lead compounds that were predicted using PASS suggest that these lead compounds possess potential anti-viral mechanisms of action for inhibiting viral replication and budding.…”

Section: Discussionsupporting

confidence: 54%

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Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Broni

Ashley

Adams

et al. 2023

IJMS

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The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina’s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of −8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (−46.97 to −118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 54%

See 1 more Smart Citation

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Broni

Ashley

Adams

et al. 2023

IJMS

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“…The binding site prediction was in agreement with that of the initial Site Finder prediction. The study also proposed higher likeliness of small molecules binding to this site [ 62 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Prospective Ebola Virus VP35 and VP40 Protein Inhibitors from Myxobacterial Natural Products

Hayat,

Gao,

Cao

et al. 2024

Biomolecules

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The Ebola virus (EBOV) is a lethal pathogen causing hemorrhagic fever syndrome which remains a global health challenge. In the EBOV, two multifunctional proteins, VP35 and VP40, have significant roles in replication, virion assembly, and budding from the cell and have been identified as druggable targets. In this study, we employed in silico methods comprising molecular docking, molecular dynamic simulations, and pharmacological properties to identify prospective drugs for inhibiting VP35 and VP40 proteins from the myxobacterial bioactive natural product repertoire. Cystobactamid 934-2, Cystobactamid 919-1, and Cittilin A bound firmly to VP35. Meanwhile, 2-Hydroxysorangiadenosine, Enhypyrazinone B, and Sorangiadenosine showed strong binding to the matrix protein VP40. Molecular dynamic simulations revealed that, among these compounds, Cystobactamid 919-1 and 2-Hydroxysorangiadenosine had stable interactions with their respective targets. Similarly, molecular mechanics Poisson–Boltzmann surface area (MMPBSA) calculations indicated close-fitting receptor binding with VP35 or VP40. These two compounds also exhibited good pharmacological properties. In conclusion, we identified Cystobactamid 919-1 and 2-Hydroxysorangiadenosine as potential ligands for EBOV that target VP35 and VP40 proteins. These findings signify an essential step in vitro and in vivo to validate their potential for EBOV inhibition.

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