In silico molecular docking, molecular dynamics simulation, and ADME study of new heterocyclic rings derived from benzimidazole as antifungal agents

Abstract

Background: Fungal infections remain a major global health concern, and increasing resistance to established antifungal agents supports the search for new chemical scaffolds. Methods: Five benzimidazole-derived heterocyclic compounds were evaluated in silico against Saccharomyces cerevisiae lanosterol 14α-demethylase (CYP51; PDB ID: 4WMZ). Molecular docking was performed using Genetic Optimization for Ligand Docking (GOLD); the highest-scoring complex was subjected to a 100 ns molecular dynamics simulation using Desmond, and pharmacokinetic properties were estimated using QikProp/SwissADME. Results: Compound 5, bearing an N(CH3)2 substituent, produced the highest PLP fitness score (93.1), exceeding fluconazole (79.6), and maintained interactions with key active-site residues and the heme environment. Molecular dynamics analysis indicated a stable protein-ligand complex over 100 ns, while root-mean-square fluctuations (RMSF) analysis showed limited fluctuations in the protein core and most ligand atoms. All designed compounds showed no Lipinski rule-of-five violations and were predicted to have high gastrointestinal absorption. Conclusion: The computational findings identify compound 5 as the most promising member of the investigated series and support further experimental evaluation of these benzimidazole-derived heterocycles as potential antifungal candidates.