Review of a Withdrawn Drug Candidate: Indiplon

Indiplon was re-evaluated as a ligand of the GABA A receptor benzodiazepine (BZ) binding site using integrated in silico approaches, including chemical-space mapping by UMAP, molecular docking, and contact-residue analysis. Chemical-space projection based on molecular fingerprints placed indiplon near clinically used GABA A hypnotics while remaining partially separated from the dense classical benzodiazepine scaffold cluster, indicating scaffold divergence within the same functional ligand class. Docking analysis at the BZ site showed energetically favorable poses for both indiplon and the reference ligand diazepam. Comparative pose inspection and residue-contact profiling revealed strong binding-mode convergence, including overlapping aromatic shelf interactions and polar anchor contacts within the pocket. Quantitative overlap of contact residues further supported spatial similarity of interaction patterns despite differences in core chemotype. These findings suggest that three-dimensional interaction geometry and pharmacophore-level alignment, rather than global scaffold identity alone, play a dominant role in BZ-site ligand recognition. Retrospective computational analysis of discontinued compounds such as indiplon may therefore provide useful structural insights and scaffold-diverse design hints for next-generation GABA A modulators.