Structure-Based Virtual Screening Identifies Sonidegib and Radotinib as Potential SPIN1 Inhibitors for Anticancer Drug Repurposing

Background: The methyllysine reader protein spindlin 1 (SPIN1) is implicated in various cancers by recognizing histone marks and modulating oncogenic pathways such as Wnt, PI3K/AKT, and RET. Despite increasing interest in SPIN1 as a therapeutic target, relatively few cell-active inhibitors have been characterized, and selectivity remains an important challenge. Therefore, developing novel SPIN1 inhibitors is needed, and drug repurposing offers a promising, time-efficient approach. Methods: This study used an integrated computational workflow to prioritize DrugBank compounds for potential interaction with SPIN1. A curated DrugBank library of 3500 compounds was screened against SPIN1 using structure-based molecular docking. Top hits were evaluated through PASS analysis to predict biological activity, followed by detailed interaction mapping, 500 ns molecular dynamics simulations, and essential dynamics to assess stability. Results: Sonidegib and Radotinib were prioritized based on docking, biological activity prediction, and interaction analyses. Comparative docking across SPIN2A, SPIN2B, SPIN3, and SPIN4 showed more favorable docking scores for SPIN1 for both prioritized compounds, whereas the reference molecule V88 showed a slightly more favorable score against SPIN2B; these differences do not establish isoform selectivity. The sampled trajectories showed that Sonidegib retained a broadly similar position in its initial binding pocket, whereas Radotinib shifted to a different binding region after 100 ns. MM-PBSA estimates showed overlapping uncertainties, and per-residue energy contributions differed between the compounds. Conclusions: These computational findings identify Sonidegib and Radotinib as candidates for experimental evaluation as potential SPIN1-binding compounds.