Important advances have been made during the last years in the understanding of the pharmacological profile of a number of drugs and toxins acting on nicotinic acetylcholine receptors (nAChRs) [1]. Among them, macrocyclic spiroimine phycotoxins have received a special attention due to their high affinity and selectivity on these receptors [2,3].In this study, ligand-based (pharmacophore generation) and structure-based (flexible docking, molecular dynamics) molecular modeling methods were used in order to better understand the structural determinants controlling the affinity and the selectivity of the interaction between these macrocyclic compounds and different subtypes of nAChRs. Among other parameters, we evaluated the role of desolvation and macrocyclic ring flexibility on the overall binding, as well as the contribution of polar and non-polar interactions for stabilizing the receptor-ligand complex. These results will constitute the basis for further structural modifications, with the design of new derivatives showing improved activity and selectivity profiles. 1. Molg� et al., Exp. Opin. Drug Discov. 2013, 8, 1203.2. Molg� et al. 'Cyclic imine toxins: chemistry, origin, metabolism, pharmacology, toxicology, and detection' in 'Seafood and freshwater toxins. Pharmacology physiology and detection', CRC Press, 2014, pp 951-990.3. Molg� et al. 'Cyclic imine neurotoxins acting on muscarinic and nicotinic acetylcholine receptors' in 'Toxins and biologically active compounds from microalgae', CRC Press, 2014, in press.

Understanding selectivity of macrocyclic spiroimine phycotoxins toward nicotinic acetylcholine receptors using ligand- and structure-based molecular modeling methods

248th National Meeting (2014)

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