Short Lysine-Containing Tripeptide as Analgesic Substance: The Possible Mechanism of Ligand-Receptor Binding to the Slow Sodium Channel.

A possible molecular mechanism of the ligand-receptor binding of Ac-Lys-Lys-Lys-NH (Ac-KKK-NH) to the Na1.8 channel that is responsible for nociceptive signal coding in the peripheral nervous system is investigated by a number of experimental and theoretical techniques. Upon Ac-KKK-NH application at 100 nM, a significant decrease in the effective charge carried by the Na1.8 channel activation gating system Z is demonstrated in the patch-clamp experiments. A strong Ac-KKK-NH analgesic effect at both the spinal and supraspinal levels is detected in vivo in the formalin test. The distances between the positively charged amino groups in the Ac-KKK-NH molecule upon binding to the Na1.8 channel are 11-12 Å, as revealed by the conformational analysis. The blind docking with the Na1.8 channel has made it possible to locate the Ac-KKK-NH binding site on the extracellular side of the voltage-sensing domain VSD. The Ac-KKK-NH amino groups are shown to form ionic bonds with Asp151 and Glu157 and a hydrogen bond with Thr161, which affects the coordinated movement of the voltage sensor up and down, thus modulating the Z value. According to the results presented, Ac-KKK-NH is a promising candidate for the role of an analgesic medicinal substance that can be applied for pain relief in humans.