Molecular modeling of the monoamine transporters and their interactions with psychostimulants and other substances

Abstract

The monoamines (i.e., dopamine, serotonin, and norepinephrine) are vital to the ontogeny, function, and plasticity of the nervous system. These neurotransmitters affect each other and regulate, amongst others, motor function, cognitive state, motivation, and stress reactions. The neurotransmission is mainly terminated by reuptake in monoamine transporters (MATs), i.e., the dopamine-, serotonin-, and norepinephrine transporter. These transporters are the focus of the current study. Imbalance in the monoamine systems in the central nervous system (CNS) is associated with neurological- and psychiatric disorders, where the MATs are targets for several therapeutic drugs. Most of these drugs bind the outward-facing conformation of the MATs, and their effects depend highly on the selectivity for a single MAT. On the other hand, the increased use of illicit stimulants, predominantly acting on DAT, has risen alarms due to their unpredictable effects and high abuse potential. Regarding this, some research standards (atypical inhibitors), suggested to bind the inward-facing conformation of the MATs, have been shown to exert anti-addictive properties – being valuable in future treatment of addiction and withdrawal symptoms. The main aim of this thesis was to construct outward-and inward facing human MAT-models, based on homology modeling, to identify determinants for selective binding to each MAT, by utilizing induced fit docking and molecular dynamics simulations. Therapeutic psychostimulants, illicit psychostimulants, antidepressants, non-stimulants, atypical inhibitors, and some research standards were studied. The results indicate that divergent residues in the S1-site play a key role in MAT-selectivity. These residues shape the polarity and steric environment in the orthosteric (S1) pocket, thus affecting the stabilization, interactions, and orientation of ligands in each MAT. Structural features in the ligands appeared to also play a role in the selectivity for a MAT, concerning the binding mode and formation of interactions.