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<p>The lethal Marburg virus has resurfaced in recent times, leading to outbreaks in Guinea in 2021, Ghana in July 2022, and Equatorial Guinea in 2023. This necessitates the development of new therapeutic agents for improved disease management. Consequently, we explored the abundant and diverse array of African pharmacophore compounds, which could offer a range of treatment alternatives and potentially aid in disease prevention and control. This study targets the Marburg nucleoprotein (Marburg-NP, PDB ID: 5F5M) using a computational approach to identify potential inhibitors from African pharmacophore compounds. We screened 10,925 compounds from African natural product databases (CONMEDNP, EANPDB, NANPDB, SANPDB) via molecular docking, identifying 21 compounds with higher binding affinities than the reference molecule, 18beta-glycyrrhetinic acid (-7.7 kcal/mol). Among these compounds, DAF2 exhibited the highest binding affinity (-9.8 kcal/mol). Additionally, we assessed their ADMET predictions and drug-likeness properties to evaluate their therapeutic potential. DAF2 and JFAUY0841 displayed more favorable and satisfactory predictions than 18 beta-glycyrrhetinic acid. Furthermore, we performed 100-nanosecond molecular dynamics (MD) simulations for the top two compounds and the reference molecule. The results revealed that DAF2 exhibits good stability with Marburg-NP. Structural stability analyses demonstrated that all systems exhibited favorable conformational stability combined with minimal protein perturbation and a conserved binding mode across all simulations. The DFT-indicated reactivity of DAF2 versus the stability of JFAUY0841 highlights a key consideration in drug design, where chemical stability typically ensures in vivo function, but controlled reactivity offers specific benefits such as prodrug activation or targeted covalent inhibition. The positive outcomes from molecular docking, ADMET predictions, MD simulations, and DFT calculations substantiate the potential of DAF2 and JFAUY0841 for further exploration in in vitro and in vivo experiments.</p>

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Novel agents inhibiting the Marburg nucleoprotein using molecular docking, ADMET, MD, and quantum DFT methods

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月7日

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  • Haiwang Djefoulna Victorien Hermann,
  • Fifen Jean Jules,
  • Conradie Jeanet

摘要

The lethal Marburg virus has resurfaced in recent times, leading to outbreaks in Guinea in 2021, Ghana in July 2022, and Equatorial Guinea in 2023. This necessitates the development of new therapeutic agents for improved disease management. Consequently, we explored the abundant and diverse array of African pharmacophore compounds, which could offer a range of treatment alternatives and potentially aid in disease prevention and control. This study targets the Marburg nucleoprotein (Marburg-NP, PDB ID: 5F5M) using a computational approach to identify potential inhibitors from African pharmacophore compounds. We screened 10,925 compounds from African natural product databases (CONMEDNP, EANPDB, NANPDB, SANPDB) via molecular docking, identifying 21 compounds with higher binding affinities than the reference molecule, 18beta-glycyrrhetinic acid (-7.7 kcal/mol). Among these compounds, DAF2 exhibited the highest binding affinity (-9.8 kcal/mol). Additionally, we assessed their ADMET predictions and drug-likeness properties to evaluate their therapeutic potential. DAF2 and JFAUY0841 displayed more favorable and satisfactory predictions than 18 beta-glycyrrhetinic acid. Furthermore, we performed 100-nanosecond molecular dynamics (MD) simulations for the top two compounds and the reference molecule. The results revealed that DAF2 exhibits good stability with Marburg-NP. Structural stability analyses demonstrated that all systems exhibited favorable conformational stability combined with minimal protein perturbation and a conserved binding mode across all simulations. The DFT-indicated reactivity of DAF2 versus the stability of JFAUY0841 highlights a key consideration in drug design, where chemical stability typically ensures in vivo function, but controlled reactivity offers specific benefits such as prodrug activation or targeted covalent inhibition. The positive outcomes from molecular docking, ADMET predictions, MD simulations, and DFT calculations substantiate the potential of DAF2 and JFAUY0841 for further exploration in in vitro and in vivo experiments.