Molecular modelling of interactions between antipsychotic drugs and receptors mediating antipsychotic effects and important side effects

Abstract

Dopamine and serotonin are two neurotransmitters that exert their actions through mediation of dopaminergic and serotonergic receptors respectively. The receptors in focus in the current study, are the dopamine D2 and serotonin 5-HT2A receptors. Common for both receptors is that they are class A G-protein-coupled receptors consisting of seven transmembrane helices embedded in the lipid membrane of neurons.

Imbalance and disruption of especially the dopamine system in the CNS may result in hallucinations, delusions, and lowered levels of motivation, which are treated with antipsychotic drugs that predominantly antagonize dopamine D2 and serotonin 5-HT2A receptors. The main aim of this thesis is to get a deeper understanding of the mechanisms of action and side effects of antipsychotics utilizing induced fit docking and molecular dynamic simulations.

Our results suggest that there is a correlation between the binding affinities of the antipsychotic drugs to different aminergic receptors, and the most common side effect observed. Additionally, MD simulations revealed that antipsychotic drugs with different intrinsic activity, bind to the dopamine D2 receptor in distinct ways.