Computational therapeutic repurposing of tavaborole targeting arginase-1 for venous leg ulcer

• Published in: Computational biology and chemistry 2024-08, Vol.111, p.108112, Article 108112
• Main Authors: Kumar V, Naveen, Tamilanban, T.
• Format: Article
• Language: English
• Subjects: Arginase; Arginase - antagonists & inhibitors; Arginase - chemistry; Arginase - metabolism; Boron Compounds - chemistry; Boron Compounds - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - metabolism; Docking; Drug Repositioning; Drug-repurposing; Dynamics; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Tavaborole; Varicose Ulcer - drug therapy; Venous leg ulcer
• ISSN: 1476-9271; 1476-928X; 1476-928X
• DOI: 10.1016/j.compbiolchem.2024.108112

Venous leg ulcers (VLUs) pose a growing healthcare challenge due to aging, obesity, and sedentary lifestyles. Despite various treatments available, addressing the complex nature of VLUs remains difficult. In this context, this study investigates repurposing boronated drugs to inhibit arginase 1 activity for VLU treatment. The molecular docking study conducted by Schrodinger GLIDE targeted the binuclear manganese cluster of arginase 1 enzyme (2PHO). Further, the ligand-protein complex was subjected to molecular dynamic studies at 500 ns in Gromacs-2019.4. Trajectory analysis was performed using the GROMACS simulation package of protein RMSD, RMSF, RG, SASA, and H-Bond. The docking study revealed intriguing results where the tavaborole showed a better docking score (-3.957 Kcal/mol) compared to the substrate L-arginine (-3.379 Kcal/mol) and standard L-norvaline (-3.141 Kcal/mol). Tavaborole interaction with aspartic acid ultimately suggests that the drug molecule binds to the catalytic site of arginase 1, potentially influencing the enzyme's function. The dynamics study revealed the compounds' stability and compactness of the protein throughout the simulation. The RMSD, RMSF, SASA, RG, inter and intra H-bond, PCA, FEL, and MMBSA studies affirmed the ligand-protein and protein complex flexibility, compactness, binding energy, van der waals energy, and solvation dynamics. These results revealed the stability and the interaction of the ligand with the catalytic site of arginase 1 enzyme, triggering the study towards the VLU treatment. [Display omitted] •Tavaborole exhibited better docking score than substrate for arginase 1.•Molecular dynamics simulations demonstrated tavaborole-arginase 1 complex stability.•Tavaborole interacts with arginase 1 catalytic site, potential inhibitor.•Repurposing tavaborole as arginase 1 inhibitor for venous leg ulcers.