Bioquímica quântica da dopamina nos receptores dopaminérgicos D2 e D3

Abstract

Dopamine is a neurotransmitter responsible for the sense of well-being, pleasure, happiness, and is associated with the reward system of the human body. These effects arise from their interaction with specific receptors located in the postsynaptic neurons. D2 and D3 receptors are considered targets in antipsychotic treatments, however, they lead to undesirable extrapyramidal effects to patients. Such effects are related to the non-selective interaction of pharmacological compounds with the two receptors. The crystallized structure of D3 and quantum biochemistry methods allow us to trace an interaction profile of these receptors with dopamine. Dopamine was submitted to molecular docking in the D2 and D3 structures, presenting higher interaction energy in D3 than D2. Molecular dynamics was performed with the most adequate pose obtained from the docking. There was little variation of dopamine RMSD throughout the dynamics, indicating system stability. The final coordinates were minimized and used for the quantum computation, adopting the MFCC methodology (Molecular Fractionation with Conjugated Caps). The calculations demonstrated the importance of Asp114/-24.92 kcal/mol (Asp110/-23.80 kcal/mol) residues on dopamine bound to D2 and D3 receptors. Other residues also presented importance, examples being: Val115 (Val111), Phe389 (Phe345) and Ile184 (Ile183). His349/-9.89 kcal/mol (His393/-2.50 kcal/mol) showed a large energy difference in bound to dopamine and, while His349 was at 2.50 Å of dopamine, His393 was at 3 Å. The bound energy differences found between some equivalent residues of the primary structure of the two proteins occurred due to the structural differences between the two structures, as well as the different conformations of dopamine in the two complexes. The total bound energy of dopamine in D2 (-70.06 kcal/mol) was practically the same as in D3 (-66.53 kcal/mol). The calculations evaluate the energy of the single bond state, taking into account bond enthalpy. This explains in part the conflict between data obtained in silico and experimental, which affirm the greater dopamine’s affinity with D3. New tests should be performed in order to more realistically explain the relationship between receptors and dopamine.