Cheminformatics Strategies Unlock Marburg Virus VP35 Inhibitors from Natural Compound Library

Abstract

The Ebola virus and its close relative, the Marburg virus, both belong to the family Filoviridae and are highly hazardous and contagious viruses. With a mortality rate ranging from 23% to 90%, depending on the specific outbreak, the development of effective antiviral interventions is crucial for reducing fatalities and mitigating the impact of Marburg virus outbreaks. In this investigation, a virtual screening approach was employed to evaluate 2042 natural compounds for their potential interactions with the VP35 protein of the Marburg virus. Average and worst binding energies were calculated for all 20 poses, and compounds that exhibited binding energies <−6 kcal/mol in both criteria were selected for further analysis. Based on binding energies, only six compounds (Estradiol benzoate, INVEGA (paliperidone), Isosilybin, Protopanaxadiol, Permethrin, and Bufalin) were selected for subsequent investigations, focusing on interaction analysis. Among these selected compounds, Estradiol benzoate, INVEGA (paliperidone), and Isosilybin showed strong hydrogen bonds, while the others did not. In this study, the compounds Myricetin, Isosilybin, and Estradiol benzoate were subjected to a molecular dynamics (MD) simulation and free binding energy calculation using MM/GBSA analysis. The reference component Myricetin served as a control. Estradiol benzoate exhibited the most stable and consistent root-mean-square deviation (RMSD) values, whereas Isosilybin showed significant fluctuations in RMSD. The compound Estradiol benzoate exhibited the lowest ΔG binding free energy (−22.89 kcal/mol), surpassing the control compound’s binding energy (−9.29 kcal/mol). Overall, this investigation suggested that Estradiol benzoate possesses favorable binding free energies, indicating a potential inhibitory mechanism against the VP35 protein of the Marburg virus. The study proposes that these natural compounds could serve as a therapeutic option for preventing Marburg virus infection. However, experimental validation is required to further corroborate these findings.

Structural and Dynamical Basis of VP35-RBD Inhibition by Marine Fungi Compounds to Combat Marburg Virus Infection

“…The PCA results provided valuable insights into the conformational changes and dynamic stability of the complexes. Our findings of minimal conformational changes in most complexes, indicating higher stability, align with the results of similar studies [18,28]. This emphasizes how important PCA is to the drug development process in order to comprehend multidimensional data and the behavior of potential drugs.…”

“…The initial virtual screening process was crucial in filtering out candidates with promising drug-like properties, leading to the identification of four compounds with high docking scores. This step is essential in computational drug discovery, as seen in previous studies where initial screenings have successfully narrowed down potential candidates from vast libraries [18,26,27]. The re-docking scores of our selected compounds were higher than that of the reference compound, myricetin, indicating a stronger affinity for the Marburg VP35 protein.…”

“…Although recent reports have highlighted MBV VP35 inhibitors like Semicochliodinol B, Stigmasterol, and Estradiol Benzoate, there is a desperate need for further research in this area [16][17][18]. The complexity and variability of the MBV suggest that a wider array of inhibitors from different sources could be beneficial in developing more effective treatment strategies.…”

Novel antiviral approaches for Marburg: a promising therapeutics in the pipeline

“…These compounds exhibit favorable binding free energies, indicating their potential to disrupt VP35 function, thereby hindering viral replication and immune evasion. However, experimental validation is necessary to confirm their efficacy as therapeutic options against Marburg virus infection ( Alsaady et al, 2023 ). Galidesivir and Favipiravir are antiviral drugs demonstrating potential in treating Marburg virus infection through distinct mechanisms.…”

“…Despite promising results, further research and clinical trials are necessary to evaluate their safety and effectiveness in humans ( Ursic-Bedoya et al, 2014 ; Ye et al, 2023 ). Host-targeting antivirals, such as T-705 (favipiravir) and remdesivir, show potential against Marburg virus through preclinical investigations ( Alsaady et al, 2023 ; Srivastava et al, 2023 ). However, no licensed medical countermeasures are available, necessitating further research and clinical trials for effective treatment development ( Kortepeter et al, 2020 ; van Eijk et al, 2023 ).…”