Novel computational and drug design strategies for the inhibition of human T-cell leukemia virus 1-associated lymphoma by Astilbin derivatives.

in Journal of biomolecular structure & dynamics by Shopnil Akash, Sajjat Mahmood, Rashel Ahamed, Imren Bayıl, Rahul Dev Bairagi, Md Rezaul Islam, Md Eram Hosen, Gabriela de Lima Menezes, Khalid S Almaary, Hiba-Allah Nafidi, Mohammed Bourhia, Lahcen Ouahmane

TLDR

  • Astilbin derivatives show promising inhibitory activities against HTLV-1-associated lymphoma, with Ligand-03 and Ligand-04 exhibiting notable binding affinity to HTLV-1 capsid protein and Ligand-05 displaying high binding affinity to HTLV-1 protease.

Abstract

Human T-cell leukemia virus 1 (HTLV-1) associated lymphoma is a devastating malignancy triggered by HTLV-1 infections. We employeda comprehensive drug design and computational strategy in this work to explore the inhibitory activitiesof Astilbin derivatives against HTLV-1-associated lymphoma. We evaluated the stability, binding affinities, and various computational analysis of Astilbin derivatives against target proteins, such as HTLV-1 main protease and HTLV-1 capsid protein. The root mean square deviation (RMSD), root mean square fluctuation, radius of gyration, hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) were applied to characterize these protein-ligand interactions further. Ligand-03 and ligand-04 exhibited notable binding affinity to HTLV-1 capsid protein, while ligand-05 displayed high binding affinity to HTLV-1 protease. MD simulation analysis revealed that ligand-03, bound to HTLV-1 capsid protein, demonstrated enhanced stability with lower RMSD values and fewer conformational changes, suggesting a promising binding orientation. Ligand-04, despite stable binding, exhibited increased structural deviations, making it less suitable. Ligand-05 demonstrated stable binding to HTLV-1 protease throughout the simulation period at 100 nanoseconds. Hydrogen bond analysis indicated that ligand-05 formed persistent hydrogen bonds with significantresidues, contributing to its stability. PCA highlighted ligand-03's more remarkable conformational changes, while DCCM showed ligand-05's distinct dynamics, indicating its different behavior in the complex. Furthermore, binding free energy calculations supported the favorable interactions of ligand-03 and ligand-04 with HTLV-1 capsid protein, while ligand-05 showed weaker interactions with HTLV-1 protease. Molecular electrostatic potential and frontier molecular orbital analyses provided insights into these compounds' charge distribution and stability. In conclusion, this research found Astilbin derivatives as potential inhibitors of HTLV-1-associated lymphoma. Future attempts at drug development will benefit from the steady interaction landscape provided by Ligand-03, Ligand-04 and Ligand-05, which showed the most attractive binding profile with the target protein. These results open up new opportunities for innovative drug development, and more experimental testing should be done between Astilbin derivatives and HTLV-1-associated lymphoma.

Overview

  • The study aimed to explore the inhibitory activities of Astilbin derivatives against HTLV-1-associated lymphoma using a comprehensive drug design and computational strategy.
  • The researchers evaluated the stability, binding affinities, and computational analysis of Astilbin derivatives against target proteins such as HTLV-1 main protease and HTLV-1 capsid protein.
  • The primary objective was to identify potential inhibitors of HTLV-1-associated lymphoma.

Comparative Analysis & Findings

  • Ligand-03 and Ligand-04 exhibited notable binding affinity to HTLV-1 capsid protein, while Ligand-05 displayed high binding affinity to HTLV-1 protease.
  • MD simulation analysis revealed that Ligand-03 bound to HTLV-1 capsid protein demonstrated enhanced stability with lower RMSD values and fewer conformational changes.
  • Binding free energy calculations supported the favorable interactions of Ligand-03 and Ligand-04 with HTLV-1 capsid protein, while Ligand-05 showed weaker interactions with HTLV-1 protease.

Implications and Future Directions

  • This study found Astilbin derivatives as potential inhibitors of HTLV-1-associated lymphoma, which opens up new opportunities for innovative drug development.
  • Future attempts at drug development will benefit from the steady interaction landscape provided by Ligand-03, Ligand-04, and Ligand-05.
  • More experimental testing should be done between Astilbin derivatives and HTLV-1-associated lymphoma to further validate these findings and explore their potential as therapeutic agents.
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