The duration of anesthesia (related to protein binding of a drug) and the onset time (determined by the pKa) are important characteristics in assessment of local anesthetic agents. They are known to be affected by a number of factors. Early studies of antiarrhythmic diterpenoid alkaloids from plants Aconitum and Delphinium suggested that they possess local anesthetic activity due to their ability to suppress sodium currents of excited membranes. In this study we utilized toxicity, duration, and onset of action as endpoints to construct Quantitative Structure-Activity Relationship (QSAR) models for the series of 34 diterpenoid alkaloids characterized by local anesthetic activity using genetic algorithm-based multiple linear regression analysis/partial least squares and simplified molecular input line entry system (SMILES)-based optimal descriptors approach. The developed QSAR models correctly reflected factors that determine three endpoints of interest. Toxicity correlates with descriptors describing partition and reactivity of compounds. The duration of anesthesia was encoded by the parameters defining the ability of a compound to bind at the receptor site. The size and number of H-bond acceptor atoms were found not to favor the speed of onset, while topographic electronic descriptor demonstrated strong positive effect on it. SMILES-based optimal descriptors approach resulted in overall improvement of models. This approach was shown to be more sensitive to structural peculiarities of molecules than regression methods. The results clearly indicate that obtained QSARs are able to provide distinct rationales for compounds optimization with respect to particular endpoint.
Keywords: QSAR; alkaloids; local anesthetic activity; optimal descriptors; toxicity.