Análise da ligação da olanzapina ao receptor humano de dopamina D3 através de cálculos quânticos

Abstract

The schizophrenia is a psychiatric disease characterized by the contact loss with the reality. The most accepted biochemistry hypothesis to explain schizophrenia is the dopaminergic hypothesis, in which it states that the excessive release of dopamine may cause or worsen several psychotic conditions. The main strategy of treatment is through the antipsychotic drugs, which act as dopamine receptor modulators. Among the agents used in clinic is Olanzapine, a second-generation atypical antipsychotic. Recently the D3 receptor has emerged as a potential target for a treatment of schizophrenia, mainly because of its therapeutic potential with a reduced incidence of extrapyramidal symptoms. In this way, understanding the mechanism of interaction of the various antipsychotics with this receptor is crucial for the development of improved therapeutic agents. In this work the three-dimensional structure of the human dopamine D3 receptor co-crystallized with the antagonist eticlopride was used to investigate, in silico, the binding profile of olanzapine, by quantum mechanics methods. Surprisingly, analysis of the protonation and balance states indicated that olanzapine, under conditions of physiological pH, is presented in two forms, one neutral (olanzapine 47) and one protonated (olanzapine 52).Thus, both states of protonation were investigated during this study. Our results indicate that residues Asp110, Val111, Phe345, Phe346, Ile183, Tyr373, Ser192, His349, Val189, Cys114 and Trp342 showed the highest binding energy values of the complexes. The total binding energy (antipsychotic-D3) was -52.2 kcal / mol for olanzapine 47 and -86.6 kcal / mol for olanzapine 52, indicating that the protonated form of olanzapine, despite being in balance with neutral form exhibits a greater tendency to interact with the dopamine D3 receptor. These results will be useful for a better understanding of the mechanisms of atypicity of some antipsychotic agents and will aid in the rational development of new drugs.