Combined Simulation and Mutation Studies to Elucidate Selectivity of Unsubstituted Amphetamine-like Cathinones at the Dopamine Transporter

Authors/others:Seddik, Amir; Geerke, Daan P (Vrije Universiteit Amsterdam); Stockner, Thomas (Medizinische Universität Wien); Holy, Marion (Medizinische Universität Wien); Kudlacek, Oliver (Medizinische Universität Wien); Cozzi, Nicholas V (University of Wisconsin, Madison); Ruoho, Arnold E (University of Wisconsin, Madison); Sitte, Harald H (Medizinische Universität Wien); Ecker, Gerhard F

The dopamine and serotonin transporter proteins (DAT, SERT) play a vital role in behavior and mental illness. Although their substrate transport has been studied extensively, the molecular basis of their selectivity is not completely understood yet. In this study, we exploit molecular dynamics simulations combined with mutagenesis studies to shed light on the driving factors for DAT-over-SERT selectivity of a set of cathinones. Results indicate that these compounds can adopt two binding modes of which one is more favorable. In addition, free energy calculations indicated the substrate binding site (S1) as the primary recognition site for these ligands. By simulating DAT with SERT-like mutations, we hypothesize unsubstituted cathinones to bind more favorably to DAT, due to a Val152 offering more space, as compared to the bulkier Ile172 in SERT. This was supported by uptake inhibition measurements, which showed an increase in activity in SERT-I172V.

Date of publication:8.11.2016
Journal title:Molecular Informatics
Peer reviewed:true
Digital Object Identifier (DOI):
Bibliographical note:© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication Type:Article