Network pharmacology, molecular docking-driven, Qbd-Engineered antifungal in-situ gel loaded with voriconazole nanostructured lipid carriers

Abstract

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

Keywords:

• Fungal infections
• voriconazole
• molecular docking
• nanostructured lipid carrier
• network pharmacology

Acknowledgments

The authors acknowledge the Vice Chancellor, IFTM University, Moradabad, India and Management of Devsthali Vidyapeeth College of Pharmacy, Rudrapur, Uttarkhand, India for providing necessary facilities for completion of this project.

Disclosure statement

The authors declare that they have no conflict of interest.

Authors’ contributions

Conceptualization A. T., V. T.; writing – original draft preparation B.P., A.T. V.T. and R. A.; writing – review and editing A.T., N. K. and M.K. All authors have read and approved the manuscript.

Availability of data and material

All data generated or analyzed during this study are included in this article and its Supplementary information.

Authors’ contributions

Conceptualization A. T., V. T.; writing – original draft preparation B.P., A.T. V.T. and R. A.; writing – review and editing A.T., N. K. and M.K. All authors have read and approved the manuscript.

Additional information

Funding

There was no particular grant for this assessment from any funding source in the public, commercial or non-profit sectors.