Docking Studies of Phthalimide Pharmacophore as a Sodium Channel Blocker

  Objective(s): Recently, phthalimide derivatives were designed based on ameltolide and thalidomide as they possess a similar degree of anticonvulsant potency due to their phenytoin-like profile. The ability of phthalimide pharmacophore to interact with neuronal voltage-dependent sodium channels was studied in the batrachotoxin affinity assay. Therefore, in the present study, a series of ۱۹ compounds of phthalimide pharmacophore possessing a variety of substituents (NO۲, NH۲ , Me, Cl, COOH, MeO) at ۲-, ۳-, and ۴- position of the N-phenyl ring and N-(۳-amino-۲-methylphenyl) succinimide, were subjected to docking studies in order to inhibit voltage-gated sodium channels.   Materials and Methods : Chemical structures of all compounds were designed using HYPERCHEM program and Conformational studies were performed through semi-empirical molecular orbital calculations method followed by PM۳ force field. Total energy gradient calculated as a root mean square (RMS) value, until the RMS gradient was ۰.۰۱ kcal mol-۱. Among all energy minima conformers, the global minimum of compounds was used in docking calculations. Using a model of the open pore of Na channels, docking study was performed by AUTODOCK۴.۲ program. Results : Docking studies have revealed that these types of ligands interacted mainly with II-S۶ residues of NaV۱.۲ through making hydrogen bonds and have additional hydrophobic interactions with domain I, II, III and IV in the channel's inner pore. Conclusion   : These computational studies have displayed that these compounds are capable of inhibiting Na channel, efficiently.