Exploring the Antifungal Activity of 1,4-Naphthoquinone Derivatives through Inhibition of Lanosterol 14-α-Demethylase: An In- Silico Approach

Fungal infections continue to represent a major global health challenge, especially in immunocompromised populations, and the increasing incidence of antifungal resistance highlights the urgent need for novel therapeutic agents. Lanosterol 14-α-demethylase (CYP51), an essential enzyme involved in fungal ergosterol biosynthesis, is a well-established target for antifungal drug discovery. The present in-silico investigation aimed to assess the antifungal potential of fourteen newly designed 1,4-naphthoquinone derivatives using molecular docking and ADMET prediction approaches. Docking studies were conducted against CYP51 (PDB ID: 4ZDY) to evaluate binding affinity and ligand–protein interactions within the active site. Most of the designed derivatives demonstrated higher binding affinity toward CYP51 than the reference antifungal drug fluconazole, with docking scores observed in the range of −8.0 to −9.2 kcal/mol. The docked complexes revealed stable binding characterized by favorable hydrophobic interactions and π–π stacking with key amino acid residues of the target enzyme. Furthermore, in-silico ADMET analysis indicated that the majority of compounds possessed acceptable drug-likeness and pharmacokinetic properties, including good intestinal absorption, limited blood–brain barrier penetration, and absence of predicted hepatotoxicity and skin sensitization. Although mutagenicity was predicted for some derivatives, several compounds exhibited an overall favorable safety and pharmacokinetic profile. In summary, the findings suggest that these 1,4-naphthoquinone derivatives are promising CYP51 inhibitors and may serve as potential lead molecules for further experimental antifungal evaluation