Modifying Olanzapine in order to Reduce Weight Gain
Abstract – Schizophrenia is a psychiatric disease that is characterized by a distorted perception of reality. There is no cure for schizophrenia, but medications are available to manage active psychotic symptoms. One of the most popular treatments for schizophrenia is an antipsychotic medication called olanzapine. While olanzapine carries many benefits, the drug is associated with weight gain, which results in increased risk for diabetes and cardiovascular disease. Olanzapine exerts its therapeutic effect by binding to the serotonin 5-hydroxytryptamine receptor 2A (5-HT2AR). If the binding of olanzapine to the 5-HT2AR target can be optimized, then a lower medication dose will be required to achieve therapeutic efficacy, thereby minimizing the side effects of treatment. The purpose of this study is to use molecular modeling and molecular docking simulations to predict the 5-HT2AR target binding energy of olanzapine and several olanzapine derivatives with lower polarity. Chemical structures were designed in Marvin Sketch, and three-dimensional structures were predicted in Avogadro. The binding of three-dimensional structures to the 5-HT2AR target was predicted using an AutoDock Vina algorithm in the Chimera platform. Five olanzapine analogs were identified that demonstrated lower binding energy to the 5-HT2AR target as compared to olanzapine. These analogs were functionalized with carbon rings of different sizes. As the size of the carbon ring in the olanzapine analog increased, the binding energy to the 5-HT2AR target decreased, up to a limit of 5 carbons, beyond which binding energy increased due to steric hindrance. These findings hold promise for the rational design of improved schizophrenia medications.