PHARMACOLOGICAL ACTIVITY AND MEMBRANE INTERACTIONS OF ANTIARRHYTHMICS- 4D-QSAR QSPR ANALYSIS/

Purpose. This study was done to explore the relationships of both macr oscopic and molecular level physicochemical properties to in-vivo anti arrhythmic activity and interactions with phospholipid membranes for a set of cationic-amphiphilic analogs. Methods. The 4D-QSAR method, rec ently developed by Hopfinger and co-workers (1), was employed to estab lish 3D-QSAR/QSPR models. Molecular dynamics simulations provided the set of conformational ensembles which were analyzed using partial leas t squares regression in combination with the Genetic Function Approxim ation algorithm to construct QSAR and QSPR models. Results. Significan t QSAR models for in-vivo antiarrhythmic activity were constructed in which logP (the partition coefficient), and specific grid cell occupan cy (spatial) descriptors are the main activity correlates. LogP is the most significant QSAR descriptor. 4D-QSPR models were also developed for two analog-membrane interaction properties, the change in a membra ne transition temperature and the ability of the analogs to displace a dsorbed Ca2+-ions from phosphatidylserine monolayers. Conclusions. Spa tial features, represented by grid cell occupancy descriptors, supplem ent partition coefficient, which is the most important determinant of in-vivo antiarrhythmic activity, to provide a comprehensive model for drug action. The QSPR models are less significant in statistical measu res, and limited to interpretation of possible molecular mechanisms of action.