Aconitum and Delphinium sp. alkaloids as antagonist modulators of voltage-gated Na+ channels: AM1/DFT electronic structure investigations and QSAR studies

Early pharmacological studies of Aconitum and Delphinium sp. alkaloids suggested that these neurotoxins act at site 2 of voltage-gated Na+ channel and allosterically modulate its function. Understanding structural requirements for these compounds to exhibit binding activity at voltage-gated Na+ channel has been important in various fields. This paper reports quantum-chemical studies and quantitative structure–activity relationships (QSARs) based on a total of 65 natural alkaloids from two plant species, which includes both blockers and openers of sodium ion channel. A series of 18 antagonist alkaloids (9 blockers and 9 openers) have been studied using AM1 and DFT computational methods in order to reveal their structure–activity (structure–toxicity) relationship at electronic level. An examination of frontier orbitals obtained for ground and protonated forms of the compounds revealed that HOMOs and LUMOs were mainly represented by nitrogen atom and benzyl/benzoylester orbitals with OH and OCOCH3 contributions. The results obtained from this research have confirmed the experimental findings suggesting that neurotoxins acting at type 2 receptor site of voltage-dependent sodium channel are activators and blockers with common structural features and differ only in efficacy. The energetic tendency of HOMO–LUMO energy gap can probably distinguish activators and blockers that have been observed. Genetic Algorithm with Multiple Linear Regression Analysis (GA-MLRA) technique was also applied for the generation of three-descriptor QSAR models for the set of 65 blockers. Additionally to the computational studies, the HOMO–LUMO gap descriptor in each obtained QSAR model has confirmed the crucial role of charge transfer in receptor–ligand interactions. A number of other descriptors such as log P, IBEG, nNH2, nHDon, nCO have been selected as complementary ones to LUMO and their role in activity alteration has also been discussed.