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

Integrated computational approach using molecular dynamics simulations and binding free energy calculations

“This study employed an integrated computational approach to evaluate the binding selectivity of KP-10 across key receptors implicated in impulsivity and compulsion.”

Kisspeptin-10 (KP-10) and its predicted binding to KISS1R, NPFF1R, D1R, D2R, 5-HT1AR, and 5-HT2AR receptors

“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.”

500 nanoseconds

“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.”

KP-10 showed the lowest binding energies for KISS1R and NPFF1R compared to dopamine and serotonin receptors

“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 supported the observed energetic trends

“Conformational stability metrics (RMSD, RMSF, Rg, and hydrogen bond occupancy) corroborated these energetic trends.”

KP-10 demonstrates high selectivity for KISS1R over monoaminergic receptors

“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.”

Experimental confirmation is required to draw firm conclusions

“However, experimental confirmation of these results is required to draw firm conclusions.”