Epsilon Archive for Student Projects

Abstract

Filarial nematode infection remains an important worldwide burden on animal and human health, exacerbated by widespread drug resistance and a slowness in the development of new anthelmintic drugs. Setaria digitata, a veterinary filarial parasite closely related to human-infective species such as Wuchereria bancrofti and Brugia malayi, presents a tractable model for investigating novel therapeutic targets. This study employed a complete bioinformatics pipeline to prioritize parasite-specific drug targets in S. digitata with a goal of avoiding limitations found in conventional drug discovery and experimental inaccessibility of human filariae.
The study integrated various computational strategies such as sub-cellular localization prediction, functional annotation, and structural modelling. After filtering for proteins likely to be specific to nematodes, a multi-criteria scoring system was developed to rank them based on predicted essentiality, drug accessibility, and relevance to known therapeutic target classes such as ion channels, microtubules, neuroreceptors, and proteases. Prediction of druggability was further augmented with the use of Fpocket and COACH-D for prediction and validation of ligand-binding sites.
From a predicted, non-redundant proteome of 12,238 gene-derived protein sequences, subcellular localization analysis indicated that approximately 18% may be pharmacologically accessible, while functional annotation via eggNOG-mapper covered 70.2% of the dataset. Prioritization integrated essentiality, conservation, and accessibility, yielding 250 high-confidence targets, 88.4% of which were neurological proteins, recapitulating known anthelmintic mechanisms (e.g., ivermectin-targeted glutamate-gated chloride channels). Structural modelling of 58 candidates identified 30 high-druggability targets, including G-protein coupled receptors (GPCRs) and ion channels. COACH-D validation confirmed ligand-binding potential for top candidates, with SD_012157-T1 exhibiting strong similarity to established drug targets (TM-score: 0.56, binding energy: −7.2 kcal/mol). These results provide a foundation for experimental validation and rational antifilarial design, with implications for both human and veterinary parasitology.