Pharmacophore Modeling of AHAS Inhibitors for Targeted Antifungal Discovery

Recent experimental studies have proven the efficacy of targeting the acetohydroxyacid synthase (AHAS) enzyme against fungal and bacterial infections. Since AHAS is a vital enzyme for plants and microorganisms but absent in animals, it offers a highly selective target with a low risk of human toxicity. Our study aims to deepen the understanding of the molecular mechanisms involved in the inhibition of this enzyme (especially in the Candida albicans strain), as well as to extract the essential features responsible for the targeted biological activity.

To this end, a suite of pharmacophore models was developed using integrated in silico methods. The approach included structure-based molecular docking techniques using the Glide module, and pharmacophore modeling via the Phase module. Structural hypotheses were built based on the specific interactions between a series of known inhibitors and key residues within the enzyme's active site.

As a result, an ensemble of 30 distinct pharmacophore hypotheses was generated, each configured to include between 3 and 5 pharmacophore features. The validation of these multiple models (including through atom-based QSAR methods and active-decoy analyses) demonstrated a high capacity to differentiate truly active compounds from inactive molecules.

The obtained validated models can be successfully used as efficient filters in virtual screening campaigns for the discovery and optimization of novel compounds with high antifungal potential. This diversified approach maximizes the chances of identifying new efficient chemical structures while simultaneously guaranteeing an optimal safety profile.