Abstract
<jats:p>Somatostatin receptor subtype 2 (SSTR2) is overexpressed in high-risk neuroblastoma stage 4 (NBS4) in patients with chromosome 17q gain, making it a potential therapeutic target. This computational study employed a multi-platform drug design workflow to identify novel SSTR2 ligands based on the selective agonist L-054,522. Using BROOD (OpenEye Scientific), 5,507 structural analogues were generated, from which 293 candidates were docked to SSTR2 (PDB: 7XN9) using FRED, HYBRID, and POSIT. Eight compounds achieved GREAT pose confidence (75-100% probability within 2.0 A of the true binding mode). Confirmatory docking with AutoDock Vina, FITTED, and Flare corroborated these results. ADMET profiling using T.E.S.T., DEEP-PK, and SwissADME indicated favourable safety profiles for all eight compounds, with no predicted mutagenicity or developmental toxicity. Retrosynthetic analysis using ChemAIRS and Spaya confirmed synthetic feasibility, with compound 8 achieving an RScore of 1.0. Compound 8 demonstrated consistent docking performance across all platforms and exhibited interaction patterns, including contacts with Asp122, Gln126, and Thr194, that align with residues previously identified as critical for SSTR2 ligand binding. Molecular dynamics simulation further supported the stability of the predicted complex, showing preservation of global structural integrity with local flexibility concentrated mainly in terminal and loop regions. Exploratory docking to CRHR1 and GALR2, two additional chromosome 17q GPCRs expressed in neuroblastoma, suggested that compound 8 may occupy these binding sites, though functional consequences remain unknown. These findings identify compound 8 as a computationally prioritised lead candidate warranting experimental evaluation through binding assays and functional studies to determine its pharmacological activity at SSTR2.</jats:p>