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Volume 21, Issue 1
  • ISSN: 1573-4099
  • E-ISSN: 1875-6697

Abstract

Background

Neglected tropical diseases (NTDs) are parasitic and bacterial diseases that affect approximately 149 countries, mainly the poor population without basic sanitation. Among these, Human African Trypanosomiasis (HAT), known as sleeping sickness, shows alarming data, with treatment based on suramin and pentamidine in the initial phase and melarsoprol and eflornithine in the chronic phase. Thus, to discover new drugs, several studies point to rhodesain as a promising drug target due to the function of protein degradation and intracellular transport of proteins between the insect and host cells and is present in all cycle phases of the parasite.

Methods

Here, based on the previous studies by Nascimento (2021) [5], that show the main rhodesain inhibitors development in the last decade, molecular docking and dynamics were applied in these inhibitors datasets to reveal crucial information that can be into drug design.

Results

Also, our findings using MD simulations and MM-PBSA calculations confirmed Gly19, Gly23, Gly65, Asp161, and Trp184, showing high binding energy (G between -72.782 to -124.477 kJ.mol-1). In addition, Van der Waals interactions have a better contribution (-140,930 to -96,988 kJ.mol-1) than electrostatic forces (-43,270 to -6,854 kJ.mol-1), indicating Van der Waals interactions are the leading forces in forming and maintaining ligand-rhodesain complexes. Thus, conventional and covalent docking was employed and highlighted the presence of Michael acceptors in the ligands in a peptidomimetics scaffold, and interaction with Gly19, Gly23, Gly65, Asp161, and Trp184 is essential to the inhibiting activity. Furthermore, the Dynamic Cross-Correlation Maps (DCCM) show more correlated movements for all complexes than the free rhodesain and strong interactions in the regions of the aforementioned residues. Principal Component Analysis (PCA) demonstrates complex stability corroborating with RMSF and RMSD.

Conclusion

This study can provide valuable insights that can guide researchers worldwide to discover a new promising drug against HAT.

© 2025 Bentham Science Publishers
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2024-11-26

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Insights to Design New Drugs against Human African Trypanosomiasis Targeting Rhodesain using Covalent Docking, Molecular Dynamics Simulations, and MM-PBSA Calculations
Curr. Computeraided Drug Des. 21, 67 (2025); https://doi.org/10.2174/0115734099274797231205055827
/content/journals/cad/10.2174/0115734099274797231205055827
/content/journals/cad/10.2174/0115734099274797231205055827
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  • Article Type:     Research Article
Keyword(s): Human african trypanosomiasis; MM-PBSA calculations; molecular docking; molecular dynamics; molecular modeling; rhodesain; sleeping sickness

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