Structure-Guided Framework for Characterizing Drug Resistance-Mediating ABC Transporters in Coccidioides immitis

Avelyn Jing

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Keywords: ABC transporters, AlphaFold2, antifungal resistance, Coccidioides immitis, molecular dynamics, Valley fever

TL;DR: This study introduces a structure-guided framework and the first dataset characterizing ABC transporters in Coccidioides immitis, enabling early-stage pocket screening and AI-guided precision antifungal therapy development.

Abstract: The increasing incidence of drug resistance and the spread of fungal diseases underscore the urgent need to investigate resistance mechanisms in Valley fever, a fungal infection caused by Coccidioides spp. that has increased sharply in recent years and mirrors broader antifungal resistance trends. ATP-binding cassette (ABC) transporters, which are shown to efflux drugs in well-studied fungi, remain structurally uncharacterized in Coccidioides immitis. This study proposes the first structure-guided framework for systematic binding pocket assessment and inhibitor testing across five C. immitis ABC transporters. High-confidence protein structures (mean pLDDT > 95) were predicted using AlphaFold2, and predicted pockets were identified using PrankWeb. AutoDock Vina docked five chemically diverse ligands, generating 520 protein-ligand-pocket complexes. Static filtering (based on docking scores and pocket probability) and reference protein alignment created a shortlist of 26 complexes, which underwent short explicit-solvent MD simulations to assess binding persistence. Ligand center-of-mass drift was used to evaluate binding retention, and 17 pockets with minimal drift were given the initial classification as stable within the 2 ns MD window. Extended 20 ns simulations on a representative subset confirmed that early-screened stable pockets generally persisted, validating the use of 2 ns MD as a pocket prioritization strategy. This work provides the first structural dynamics dataset for C. immitis ABC transporters, identifies promising binding pockets, and highlights milbemycin oxime as a consistent binder. The presented framework enables early-stage screening and filtering for pocket prioritization in fungal resistance–mediating ABC transporters, supporting precision antifungal development through a structure-guided analysis of transporter pockets.

Track: 7. General Track

Registration Id: XDN5KHV982R

Submission Number: 220