Exploring quinoline-type inhibitors of ergosterol biosynthesis: Binding mechanism investigation via molecular docking, pharmacophore mapping, and dynamics simulation approaches.

Abstract

Drug-resistant fungal infections pose a formidable challenge in healthcare, attributed to ergosterol production as a key mechanism of resistance. It is therefore imperative to target this pathway for effective therapeutic interventions. In this study, we have analyzed the binding mode of twelve quinoline derivatives known to be effective against various Candida species, Microsporum gypseum, and Cryptococcus neoformans. Employing molecular docking techniques, pharmacological modeling, and molecular dynamics, we have delved into interactions with Erg1, Erg11, and Erg24 proteins, crucial in ergosterol biosynthesis. Our analysis unveiled critical interactions that facilitate the docking and stabilization of C-2-substituted quinoline derivatives on these proteins, highlighting their potential as regulators of ergosterol synthesis. Furthermore, complexes formed with Erg1 ^… 8 (MIC = 125 μg/mL) and Erg24 ^… 4 (MIC = 62 μg/mL) showed higher affinity and stability during the docking process, pointing to their promising role as regulatory agents of these proteins. This in silico approach provides insights into potential pathways to combat drug-resistant fungal infections.