In silico characterisation of C11orf42 as a potential therapeutic target in triple-negative breast cancer

Triple-negative breast cancer (TNBC) lacks actionable targets and rapidly develops resistance; therefore, we used an integrative in silico approach to functionally characterise C11orf42 and assess its therapeutic relevance. Sequence and structural analyses revealed that C11orf42 is a ∼36.4 kDa soluble cytosolic protein composed of a conserved TED domain (residues 14-213; mean pLDDT ≈ 89) and a flexible intrinsically disordered C-terminal region (residues ∼232-333). Intrinsic disorder supports conformational flexibility; however, specific functional roles (e.g., protein-protein interaction scaffolding or signalling) remain hypothesis-generating and require orthogonal validation. Protein-protein interaction network analysis identified a highly enriched network (71 nodes, 432 edges; p < 1.0 × 10⁻¹⁶), implicating C11orf42 in vesicular trafficking, receptor recycling, and oncogenic signalling pathways relevant to TNBC. Structure-based druggability analysis revealed four ligandable pockets, and molecular docking identified four phytochemicals-chamaejasmin, Genetin J, isomultiflorenol, and podocarpusflavone B-with favorable binding affinities (≈ -8.9 to -9.6 kcal/mol). In 100-ns MD simulations, the full-length protein showed RMSD ∼10-12 Å due to C-terminal disorder, while the TED core (residues ∼14-213) remained stable at 2-3 Å. In-silico profiling indicates Chamaejasmin is a beyond-Ro5, high-affinity, long-residence C11orf42 inhibitor (t½ = 118.07 h; logP = 2.87) with acceptable safety but poor solubility (logS = -6.36), limited oral bioavailability (39.98 %), and multiple drug-likeness violations, making formulation/scaffold optimisation the main barrier. Importantly, functional genomics analysis of DepMap CRISPR-Cas9 screening data shows that C11orf42 is not a pan-essential viability gene but displays a context-restricted dependency profile, consistent with a regulatory or modulatory role rather than a core survival function. Collectively, these results prioritise C11orf42 as a computationally inferred, conditionally relevant regulatory candidate for further experimental evaluation in TNBC and provide a hypothesis-generating structural, network, and functional framework for future validation.