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Volume 20, Issue 1
  • ISSN: 1573-4099
  • E-ISSN: 1875-6697

Abstract

Introduction

Integration of viral DNA into the host cell genome, carried out by the HTLV-1 integrase enzyme, is a crucial step in the Human T-lymphotropic Virus type I (HTLV-1) life cycle. Thus, HTLV-1 integrase is considered an attractive therapeutic target; however, no clinically effective inhibitors are available to treat HTLV-1 infection.

Objective

The main objective was to identify potential drug-like compounds capable of effectively inhibiting HTLV-1 integrase activity.

Methods

In this study, a model of HTLV-1 integrase structure and three integrase inhibitors (dolutegravir, raltegravir, and elvitegravir as scaffolds) were used for designing new inhibitors. Designed molecules were used as templates for virtual screening to retrieve new inhibitors from PubChem, ZINC15, and ChEMBL databases. Drug-likeness and docked energy of the molecules were investigated using the SWISS-ADME portal and GOLD software. Stability and binding energy of the complexes were further investigated using molecular dynamic (MD) simulation.

Results

Four novel potential inhibitors were developed using a structure-based design protocol and three compounds from virtual screening. They formed hydrogen bonding interactions with critical residues Asp69, Asp12, Tyr96, Tyr143, Gln146, Ile13, and Glu105. In addition, π stacking, halogen, and hydrogen bond interactions were seen between compounds (especially halogenated benzyl moieties) and viral DNA similar to those seen in parent molecules. MD simulation confirmed higher stability of the receptor-ligand complex than the ligand-free enzyme.

Conclusion

Combing structure-based design and virtual screening resulted in identifying three drug-like molecules (PubChem CID_138739497, _70381610, and _140084032) that are suggested as lead compounds for developing effective drugs targeting HTLV-1 integrase enzyme.

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2024-01-01
2025-05-23

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Development of Potential Inhibitors for Human T-lymphotropic Virus Type I Integrase Enzyme: A Molecular Modeling Approach
Curr. Computeraided Drug Des. 20, 72 (2024); https://doi.org/10.2174/1573409919666230419082839
/content/journals/cad/10.2174/1573409919666230419082839
/content/journals/cad/10.2174/1573409919666230419082839
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  • Article Type:     Research Article
Keyword(s): HTLV-1; integrase; integrase inhibitors; ligand-based design; structure-based design; virtual screening

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