Structure-based design, in silico profiling, and synthesis of thiophene and cyanopyridine derivatives as μ-opioid receptor ligand candidates

The μ-opioid receptor (MOR) is a central target in pain-related signaling, and structure-based workflows can accelerate the identification of high-affinity MOR ligand candidates. Here, we designed a focused series of thiophene- and (cyano)pyridine-modified derivatives inspired by naloxone/naltrexone/oxycodone scaffolds and prioritized them computationally. To reduce state-dependent bias and assess binding robustness, docking was performed against both inactive (antagonist-bound) and active (agonist-bound) MOR conformations, and top-ranked hits were further refined using induced-fit docking (IFD). The refined candidates exhibited binding modes consistent with key MOR recognition features, reaching IFD docking scores as low as −13.49 kcal/mol (e.g., Naltrexone 6, NH + , in the active-state MOR structure 5C1M). Physicochemical/ADME profiling (QikProp) and QSAR modeling were used to support prioritization and highlight structure–property/activity trends. Twelve prioritized candidates were synthesized via thiophene and cyanopyridine functionalization, obtained in moderate-to-excellent yields (up to 89%), and structurally confirmed by NMR and elemental analysis.