HANSEN: An Integrated Structural and Functional Proteome Resource for Structure-Guided Drug Discovery in Mycobacterium leprae

Structural biology has advanced antimicrobial discovery by enabling drug-target identification and validation and supporting structure-guided inhibitor design. However, Mycobacterium leprae (M. leprae), the obligate intracellular bacillus that causes leprosy (Hansen's disease), remains structurally under-characterised. Only 10 Protein Data Bank (PDB) entries represent seven unique proteins within a proteome encoded by 1,603 protein-coding genes. To address this gap, we present HANSEN (https://hansen-leprosy.medschl.cam.ac.uk/home), an integrated structural and functional resource containing computationally predicted three-dimensional models across the M. leprae proteome. Monomeric and oligomeric models were generated using complementary structure-prediction methods, including AlphaFold 3, Boltz-1, Chai-1, and Boltz-2. Models were annotated with predicted Local Distance Difference Test (pLDDT) scores and Predicted Aligned Error (PAE) values. Ligand-binding pockets were predicted using AF2BIND, P2Rank, and fpocket, and ligands from the best-matching PDB templates were modelled within oligomeric complexes. Residue-level B-cell epitope propensity was estimated using DiscoTope-3.0, and ProteomeLM-derived essentiality scores were calculated for each protein. These features were integrated into a relational web database with interactive visualisation through Mol*. We also ranked all 1,603 proteins using a Target Priority Score ranging from 0 to 100. The score combines ProteomeLM-derived essentiality with pocket and AF2BIND predictions, functional annotations, and Boltz-2-associated measures of model quality and tractability. The essentiality model used a logistic-regression head trained on Mycobacterium tuberculosis (M. tuberculosis) Tn-seq labels. It achieved an AUROC of 0.84 in homology-grouped M. tuberculosis cross-validation and a transfer AUROC of 0.78 against the orthologue-aligned M. leprae reference set. Proteins were assigned to four tiers, ranging from high priority to exploratory candidates. Together, HANSEN provides a practical resource for generating and prioritising experimentally testable hypotheses for M. leprae target discovery and structure-guided drug development.