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

Authors

Maria A Netesa, Sarng S Pyurveev, Andrei A Lebedev, Eugenii R Bychkov, Ekaterina V Skorb, Sergey Shityakov, Petr D Shabanov

Published in

In silico pharmacology. Volume 14. Issue 3. Pages 223. Epub Sep 06, 2026.

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 (ΔG_GB =- 158.3 ± 6.9 kcal/mol), followed by NPFF1R (ΔG_GB =- 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.
The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00726-0.

PMID:
42707558
Bibliographic data and abstract were imported from PubMed on 08 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.