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

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.

Communicated by Ramaswamy H. Sarma

Keywords:

• Lymphoma
• molecular docking
• molecular dynamic simulation
• ADMET
• PCA

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgment

The authors extend their appreciation to the Researchers Supporting Project number (RSP2023R189), King Saud University, Riyadh, Saudi Arabia.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contributions

Conceptualization, writing the original draft, formal analysis: Shopnil Akash, Sajjat Mahmood, Rashel Ahamed, Imren Bayıl. investigations, funding acquisition, resources, project administration, Rahul Dev Bairagi, Md. Rezaul Islam, Md. Eram Hosen, Khalid S. Almaary. Reviewing and editing, data validation and data curation: Hiba-Allah Nafidi8, Mohammed Bourhia, Lahcen Ouahmane, Gabriela de Lima Menezes. All authors contributed to the article and approved the submitted version.

Additional information

Funding

This work is funded by the Researchers Supporting Project number (RSP2023R189), King Saud University, Riyadh, Saudi Arabia.