Structural basis for Kisspeptin-10 selectivity toward KISS1R: computational insights.

ABSTRACT: Kisspeptin-10 (KP-10), the bioactive core fragment of kisspeptin neuropeptides, has emerged as a modulator of reward-related behaviors beyond its canonical role in reproductive neuroendocrinology. While behavioral studies indicate that KP-10 promotes impulsive and compulsive-like phenotypes in rodent models, the molecular mechanisms underlying these effects remain unclear. This study employed an integrated computational approach to evaluate the binding selectivity of KP-10 across key receptors implicated in impulsivity and compulsion. Three-dimensional structures of KP-10 bound to kisspeptin receptor 1 (KISS1R), neuropeptide FF receptor 1 (NPFF1R), dopamine D1/D2 receptors (D1R/D2R), and serotonin 5-HT1A/2A receptors (5-HT1AR/5-HT2AR) were predicted via AlphaFold2 and embedded in lipid bilayers for 500-ns molecular dynamics simulations. Binding free energies calculated via the implicit solvation method revealed the lowest binding energies for KISS1R (ΔGGB =- 158.3 ± 6.9 kcal/mol), followed by NPFF1R (ΔGGB =- 155.5 ± 10.0 kcal/mol), with substantially weaker interactions for 5-HT1AR (- 136.5 ± 9.2 kcal/mol), D2R (- 115.9 ± 9.5 kcal/mol), and 5-HT2AR (- 111.1 ± 9.3 kcal/mol). Conformational stability metrics (RMSD, RMSF, Rg, and hydrogen bond occupancy) corroborated these energetic trends. These results demonstrate the high selectivity of KP-10 for KISS1R compared to the following monoaminergic receptors: dopamine types 1 and 2 and serotonin types 1A and 2A, suggesting that its effects on impulsive and compulsive behavior occur primarily through canonical kisspeptin signaling rather than through direct modulation of these receptors. However, experimental confirmation of these results is required to draw firm conclusions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00726-0.