Voltage-gated Na+ channel ligands and ATP: relative molecular similarity and implications for channel function

The voltage-gated sodium channel (VGNC) is targeted by naturally occurring ligands and drugs of diverse structure. ATP modulates VGNC current in-vitro but is given little prominence in models describing channel function. This computational study uses superimposition and molecular fitting to investigate relative molecular similarity within the structures of ATP and VGNC ligands. A motif of 3 linked atoms (C-N-C) in the adenine ring of ATP satisfies the fitting of a wide range of anticonvulsant structures. An alternative group (N-C-N) provides one fitting motif for the ester and amide groups of local anaesthetic drugs; protonated amine and aromatic groups in the same conformers fit to a second motif in the adenine ring. Analogous structures from other drug classes with VGNC blocking activity give the same molecular fits to ATP. Structures fitted to the adenine ring of ATP occlude the intra-molecular space between the nucleoside and triphosphate chain in approximation to their established blocking, activating or neutral effects on Na+ current. The findings are discussed in terms of drug preferences for VGNC states and channel requirements for ATP.