Can docking-score differences support 5-HT2A/5-HT2B subtype-selectivity decisions? An audited paired benchmark.

Abstract

Subtype selectivity is a paired drug-design property, and some structure-based studies infer it from score comparisons across receptors without directly validating the score difference against paired experimental selectivity. We evaluated Vina-family docking-score differences in an audited 5-HT2A/5-HT2B benchmark comprising 419 same-endpoint paired activity records, 413 unique compounds, and 411 docking-complete compounds across two structures per subtype. Experimental selectivity was ΔpX = pX(5-HT2A) - pX(5-HT2B), and docking selectivity was Δscore = mean score(5-HT2B) - mean score(5-HT2A), so positive values favored 5-HT2A. Vina Δscore gave Pearson r = 0.097 (95% confidence interval 0.020 to 0.173) and Spearman ρ = 0.057 (95% confidence interval - 0.039 to 0.151); both intervals lay below the predefined |r| = 0.20 practical threshold. Strong-selectivity discrimination gave an area under the receiver-operating-characteristic curve of 0.544 (95% confidence interval 0.427 to 0.664). The continuous association weakened with alternative scoring and disappeared after full Vinardo redocking. Under scaffold cross-validation, descriptor-plus-docking was indistinguishable from its ligand-only baseline. Fingerprint-plus-docking reduced error by 0.037 pX (ΔRMSE = - 0.037, 95% confidence interval - 0.051 to - 0.023); the point estimate was below the 0.05 pX practical threshold, although the interval narrowly reached it. Within this fixed, ligand-context-asymmetric, non-transducer-bound four-structure benchmark, Vina-family score-level features provide hypothesis-generating evidence rather than convincing stand-alone support for 5-HT2A/5-HT2B selectivity decisions.

Supplementary information: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00745-x.