In Silico Evaluation of Benzimidazole-Derived Heterocycles as CYP51-Targeting Antifungal Agent: Molecular Docking, Dynamics, and ADME Analysis
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Abstract
To counter the rising clinical threat of azole-resistant strains of Candida albicans, here, the design and computational validation of new benzimidazole-based heterocycles designed to inhibit the enzyme CYP51 is investigated. Employing a combination of GOLD-dependent molecular docking and 200-nanosecond-long Desmond molecular dynamics simulations, we were able to identify lead candidates, i.e.,
compounds with bulky substituents, with significantly higher binding affinity when compared to the clinical reference, fluconazole, exploiting deep hydrophobic sub-pockets in the active site. The observed structural stability of the MD trajectories, together with a lack of Lipinski rule violations in the ADMET profiling using QikProp, indicates that these derivatives have the necessary drug likeness for efficacious oral delivery. Ultimately, the synergy between high-occupancy lipophilic anchors and favorable pharmacokinetic parameters positions these heterocyclic scaffolds as high-priority candidates for synthetic expansion and subsequent in vitro antifungal screening. Nonetheless, since these results are purely predictive and constrained by the in-silico character, synthetic expansion and in turn in vitro and in vivo validations must be carried out to establish their clinical efficacy and safety.
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