Aconitum and Delphinium sp. alkaloids as antagonist modulators of voltage-gated Na+ channels

Abstract

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 voltagegated 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 -OCOCH 3 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 two-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 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Author Manuscript number of other descriptors such as logP, I BEG , nNH2, nHDon, nCO have been selected as complementary ones to LUMO and their role in activity alteration has also been discussed. HHS Public Access

Estimation of Rate Constants for Radical Degradation of Aromatic Pollutants by Density Functional Theory

“…Total energy and the energy of the highest occupied molecular orbital represent reaction activity. The energies of frontier molecular orbitals, E HOMO and E LUMO were widely used in developing the QSAR model, for studying the various mechanisms of organic compounds, such as toxicity and degradability [8] . The electrostatic descriptor qH + reflects characteristic of the charge distribution of the molecule.…”

A Ligand‐Based Approach to the Discovery of Lead‐Like Potassium Channel KV1.3 Inhibitors

“…More than 50% of the compounds experimentally tested exhibited clear a blockade of the Ca V 3.2‐mediated T‐type current (i. e. 16 out of the 38 molecules tested were active hits). Rasulev et al . reported quantum‐chemical studies and QSAR analysis for toxicity end‐points on a series of 65 diterpene alkaloids, which comprised blockers and activators of sodium ion channels.…”

“…More than 50% of the compounds experimentally tested exhibited clear a blockade of the Ca V 3.2-mediated T-type current (i. e. 16 out of the 38 molecules tested were active hits). Rasulev et al [33] reported quantum-chemical studies and QSAR analysis for toxicity end-points on a series of 65 diterpene alkaloids, which comprised blockers and activators of sodium ion channels. The authors concluded that the energetic tendency of HOMO-LUMO energy gap helps to distinguish between activators and blockers (where HOMO and LUMO are the energies of highest occupied molecular orbital and lowest unoccupied molecular orbital, respectively).…”

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