Design and In Silico Evaluation of Novel 1,3,4-Oxadiazole Derivatives as Potential CYP51B Inhibitors Against Aspergillus fumigatus

Abstract

Antifungal resistance and invasive fungal infections remain the major therapeutic issues, especially in patients with impaired immune systems. Aspergillus fumigatus is the main cause of invasive aspergillosis and sterol 14-α-demethylase (CYP51B), a key enzyme in the biosynthetic pathway of ergosterol, is an important target for antifungal therapy. In the present study, four new 1,3,4-oxadiazole derivatives (SH1–SH4) were designed and assessed as possible inhibitors of A. fumigatus CYP51B (PDB ID: 6CR2) by an integrated in silico approach. Binding affinity and interaction patterns within the active site were investigated using the Glide module of the Schrödinger suite. The docking scores of designed compounds ranged from −7.52 to −9.61 kcal/mol. SH4 exhibited the highest docking score (−9.61 kcal/mol), which was very close to Econazole (−9.599 kcal/mol) and better than Clotrimazole and Ketoconazole. SwissADME showed good drug-like property, high gastrointestinal absorption and follow Lipinski’s rule of five. The stability of the SH4–CYP51B complex was also confirmed by 200 ns molecular dynamics simulation in which the protein–ligand interactions remained consistent throughout the simulation. These results indicate that SH4 is a promising oxadiazole-based lead compound for further development of antifungal drugs targeting A. fumigatus CYP51B.