Olanzapine manipulates neuroactive signals and may onset metabolic disturbances

Abstract

Olanzapine is one of the most prescribed atypical antipsychotics to treat psychiatric illness and is associated with weight gain and metabolic disturbance. The present study investigated the olanzapine-regulated metabolic pathways using functional enrichent analysis including binding affinity with G-protein-coupled receptors (GPCRs). Proteins modulated by olanzapine were retrieved from SwissTargetPrediction, DIGEP-Pred, and BindingDB and then enriched in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to assess molecular function, biological process, and cellular components including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We used homology modeling to improve the 3D structure for GPCR synapse proteins including dopamine, serotonin, muscarinic, and histamine receptors which were then optimized using molecular dynamics (MD) simulations. The protein-olanzapine binding mechanisms for different GPCR binders were evaluated using molecular docking; later refined by MD simulations. Binding mechanism of olanzapine with D2, 5HT1A, 5HT2A, 5HT2B, 5HT2C, M1, and M2 receptors were created using homology modeling and optimized using MD simulations. In target identification, it was observed that olanzapine majority targeted G-protein coupled receptors. Further, enrichment analysis identified around 76% of the total genes regulated in molecular function, biological process, and cellular components were common including KEGG pathways. Moreover, it was observed that olanzapine had a major potency over the neurotransmitter synapse including neuroactive signals . Olanzapine-induced weight gain and metabolic alterations could be due to the deregulation of multiple synapses like dopamine, serotonin, muscarinic, and histamine at the feeding center followed by cGMP-PKG, cAMP, and PI3K-Akt signaling pathways. HIGHLIGHTS Olanzapine is used in the management of psychiatric illnesses. Olanzapine causes disturbance in lipids and glucosehomeostasis and manipulates energy expenditure. Olanzapine-induced weight gain may occur due to the deregulation of the multiple synapse and cGMP-PKG, cAMP, and PI3K-Akt signaling pathway Communicated by Ramaswamy H. Sarma