RESUMO
Fungal infections (FIs) affect majority of the population, but the current treatments face challenges in terms of their effectiveness. This study focused on specific fungal targets, including dihydrofolate reductase (DHFR), acetohydroxy-acid synthase (AHAS), farnesyltransferase and endoglucanase. The docking studies were conducted with the drug voriconazole (VCZ), comparing it with Fluconazole (FCZ) and Amphotericin B (ATB) against 11 protein data bank (PDB) IDs (IDYR, 3NZB, 6DEQ, 1KS5, 7T0C, 1FY4, 5AJH, 7R79, 6TZ6 and 6IDY). Molecular dynamics (MD) analysis, including RMSD, RMSF, PCA and FEL, confirmed the stability of VCZ. The solubility of VCZ was a problem, so nanostructured lipid carriers (NLCs) were developed to improve ocular penetration. VCF5 was the optimized formulation by using 32 full factorial design. VCZF5-NLCs were the best in terms of nanoparticle size (126.6 nm), Zeta potential (33.5 mV), drug content (DC; 97.38 ± 0.210), encapsulation efficiency (EE; 88.01 ± 0.272) and extended drug release. The results of the ex-vivo corneal diffusion study indicate that VCZ-NLC-loaded in-situ gel (VCZ-NLC-IG3) exhibited DC of 88.25% and drug entrapment (DE) of 74.2%. The results of the zone of inhibition indicated that VCZ-NLC-IG3 had superior efficacy compared to ATB. Network pharmacology showed VCZ interacts with the genes which are responsible for fungus ergosterol biosynthesis, including lanosterol 14-alpha demethylase inhibitors (ERG11), ergosterol biosynthesis protein 5 (ERG5), dimethylallyltransferase 2 (DIT2), ketosynthase (KCN), methylsterol monooxygenase (MSMO1), lamin B receptor (LBR), squalene epoxidase (SQLE), 3-hydroxy-3-methylglutaryl-coenzyme A Reductase (MGCR), 3-hydroxy-3-methylglutaryl-coenzyme A Synthase (HMGCS) and 3-keto-steroid reductase (HSD17B7). In conclusion, the optimized VCZ-loaded NLCs present a promising approach to treat ocular FIs.Communicated by Ramaswamy H. Sarma.
