Investigation of the Selectivity of One Type of Small-Molecule Inhibitor for Three Na

Fan Zhao, Wei Jin, Lin Ma, Jian-Ye Zhang, Jin-Long Wang, Jing-Hai Zhang, Yong-Bo Song

J Biomol Struct Dyn. 2019 Feb;37(3):702-713.

PMID: 29448911

Abstract:

Voltage-gated sodium (Nav) channels play a pivotal role for the changes in membrane potential and belong to large membrane proteins that compose four voltage sensor domains (VSD1-4). In this study, we describe the binding mode and selectivity of one of the aryl sulfonamide sodium channel inhibitors, PF-04856264, for the VSD4s in Nav1.4, Nav1.5 and Nav1.7, respectively, through molecular dynamics simulation and enhanced post-dynamics analyses. Our results show that there are three binding site regions (BSR1-3) in the combination of the ligand and receptors, of which BSR1 and BSR3 contribute to the selectivity and affinity of the ligand to the receptor. What's more, the 39th residue (Y39 in VSD4hNav1.4/ VSD4hNav1.7 and A39 in VSD4hNav1.5) and N42 in BSR1, the 84th residue (L84 in VSD4hNav1.4, T84 in VSD4hNav1.5, and M84 in VSD4hNav1.7) in BSR2 and the conserved positive charged residues in BSR3 have major contributions to the interaction between the ligand and receptor. Further analysis reveals that if the 39th residue has a benzene ring structure, the connection of BSR1 and the ligand would be much stronger through π-stacking interaction. On the other hand, the strength and number of the hydrogen bonds formed by the ligand and the conserved arginines on S4 determine the contribution of BSR3 to the total free binding energy. We anticipate this study pave the way for the design of more effective and safe treatment for pain that selectively target Nav1.7.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1235397053	PF-04856264		1235397-05-3	Price