Discovery of Galangin Derivatives as a Potential T-cell Leukemia Virus 1 Protease Inhibitor Through Chemoinformatics Approaches

Abstract

Human T-cell leukemia virus 1 (HTLV-1) has become a life-threatening problem, infecting a significant number of people every year; however, the effective treatment options for this disease are limited. This research focuses on the development of T-cell leukemia virus 1 protease inhibitor modifying galangin, a natural phytochemical with multiple pharmacological properties. However, galangin also has disadvantages, in particular poor bioavailability and solubility. To overcome these limitations, the primary structure of galangin was modified with various functional groups and computational drug design methods were applied to develop potential inhibitors for the human T-cell leukemia virus 1 protease including Lipinski's rule, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET), quantum energetic descriptions, molecular docking, electrostatic potential analysis, binding free energy calculations, and molecular dynamics simulations. These techniques are essential in determining the stability and suitability of new drug molecules with target proteins. Molecular docking studies demonstrated that the newly modified galangin derivative exhibits the strongest binding affinity for the HTLV-1 protease. In particular, compounds 02 and 03 showed significantly stronger binding affinities. Subsequently, the two best compounds were subjected to molecular dynamics simulations over 100 ns, which provided insights into the stability and flexibility of the protein-ligand complexes. Principal component analysis, calculation of the binding free energy, and the dynamic cross-correlation matrix during the simulations provided new perspectives on conformational changes within the drug-protein complex. The newly developed galangin derivatives show promising efficacy as potential therapeutics against HTLV-1 protease. The findings of this study suggest that further experimental validation could be pursued to support new drug development in the fight against HTLV-1.

Keywords: DFT; Galangin derivatives; Human T-cell leukemia virus 1, and Molecular dynamic simulation.; Molecular docking.