Computational profiling and pharmacokinetic modelling of Febuxostat: Evaluating its potential as a therapeutic agent for diabetic wound healing

• Published in: Biochimica et biophysica acta. General subjects Vol. 1869; no. 1; p. 130735
• Main Authors: Nirenjen, S., Narayanan, J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2025
• Subjects: Animals; Cell Line; Cell Movement - drug effects; Cell Survival - drug effects; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetic wounds; Febuxostat; Febuxostat - pharmacokinetics; Febuxostat - pharmacology; Humans; Inflammation; Mice; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; MRSA infections; Vascular Endothelial Growth Factor A - metabolism; Wound healing; Wound Healing - drug effects; T2DM; MRSA infections; Diabetic wounds; Molecular dynamics; NFkB; ADMET; Molecular docking; PDB; MRSA; MD; TGF-β; GSK; Wound healing; Febuxostat; VEGF; IKK; Inflammation; RMSD; COX; TPSA; DHFR; OPLS4; TNF-α; PASS; ROS; GPCR; TIP3P; MMP-9
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130735

Diabetic wounds, a significant complication of Type 2 Diabetes Mellitus (T2DM), face delayed healing due to impaired inflammation, angiogenesis, and collagen synthesis. This study explores Febuxostat, a xanthine oxidase inhibitor for its therapeutic potential in wound healing. Combining computational approaches and in-vitro assays, the study evaluates its effects on key wound healing pathways, cell viability, migration. The potential of Febuxostat in diabetic wound healing was studied using in-silico tools for Molecular docking and ADMET profiling, alongside Molecular dynamics (MD) simulations. Toxicity was assessed with OSIRIS Explorer, and biological activity was predicted using the PASS tool. In-vitro MTT and scratch assays on L929 cells further validated cytotoxicity and wound healing efficacy. Docking analysis revealed strong binding affinities to key wound healing targets, including VEGF (−9.11 kcal/mol) and NFKβ (−8.62 kcal/mol). Pharmacokinetic studies highlighted favorable skin permeability, supporting topical applications. Toxicity predictions indicated a safe profile. Molecular dynamics simulations demonstrated stable protein-ligand complexes, particularly with VEGF. Cytotoxicity studies on L929 cells revealed an IC50 of 6.08 μM and the scratch assay demonstrated significant wound healing activity, highlighting its effectiveness in promoting cell migration and closure. Febuxostat shows remarkable potential in enhancing diabetic wound healing by promoting cell migration, targeting wound-healing proteins, as demonstrated through in-silico and in-vitro studies. This drug is poised to effectively treat diabetic wounds, accelerating healing and reducing complications. Rigorous pre-clinical and clinical evaluations are essential to validate its safety, efficacy, and therapeutic potential. •Molecular Docking and Dynamics simulations confirm Febuxostat's stable interactions with wound healing and MRSA target proteins.•Febuxostat demonstrates strong binding with VEGF, Type-1 collagen, and NF-κB, highlighting its therapeutic potential for diabetic wound healing.•The drug shows dual functionality, enhancing wound healing and exhibiting antimicrobial activity against MRSA alongside having a better cell viability and wound healing in L929 cell lines. [Display omitted]