Affiliation:
1. Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse–Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
Abstract
Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT.
Funder
National Institute on Drug Abuse–Intramural Research Program
Reference56 articles.
1. SLC6 neurotransmitter transporters: Structure, function, and regulation;Kristensen;Pharmacol. Rev.,2011
2. Nonclassical pharmacology of the dopamine transporter: Atypical inhibitors, allosteric modulators, and partial substrates;Schmitt;J. Pharmacol. Exp. Ther.,2013
3. Genetically determined dopamine availability predicts disposition for depression;Felten;Brain Behav.,2011
4. Monoamine transporters: From genes to behavior;Gainetdinov;Annu. Rev. Pharmacol. Toxicol.,2003
5. Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia;Kurian;J. Clin. Investig.,2009