Abstract
Risperidone is an atypical antipsychotic used in the treatment of
schizophrenia and of symptoms of irritability associated with autism
spectrum disorder (ASD). Its main action mechanism is the blockade of
D2-like receptors acting over positive and negative symptoms of
schizophrenia with small risk of extrapyramidal symptoms (EPS) at doses
corresponding to low/moderate D2 occupancy. Such a decrease in the side
effect incidence can be associated with its fast unbinding from D2
receptors in the nigrostriatal region allowing the recovery of dopamine
signaling pathways. We performed docking essays using risperidone and
the D3 receptor crystallographic data and results suggested two possible
distinct orientations for risperidone at the binding pocket. Orientation
1 is more close to the opening of the binding site and has the
6-fluoro-1,2 benzoxazole fragment toward the bottom of the D3 receptor
cleft, while orientation 2 is deeper inside the binding pocket with the
same fragment toward to the receptor surface. In order to unveil the
implications of these two binding orientations, classical molecular
dynamics and quantum biochemistry computations within the density
functional theory formalism and the molecular fractionation with
conjugate caps framework were performed. Quantum mechanics/molecular
mechanics suggests that orientation 2 (considering the contribution of
Glu90) is slightly more energetically stable than orientation 1 with the
main contribution coming from residue Asp110. The residue Glu90,
positioned at the opening of the binding site, is closer to orientation
1 than 2, suggesting that it may have a key role in stability through
attractive interaction with risperidone. Therefore, although
orientations I and 2 are both likely to occur, we suggest that the
occurrence of the first may contribute to the reduction of side effects
in patients taking risperidone due to the reduction of dopamine receptor
occupancy in the nigrostriatal region through a mechanism of fast
dissociation. The atypical effect may be obtained simply by either
delaying D3R full blockage by spatial hindrance of orientation 1 at the
binding site or through an effective blockade followed by orientation 1
fast dissociation. While the molecular interpretation suggested in this
work shed some light on the potential molecular mechanisms accounting
for the. reduced extrapyramidal symptoms observed during risperidone
treatment, further studies are necessary in order to evaluate the
implications of both orientations during the receptor
activation/inhibition. Altogether these data highlight important hot
spots in the dopamine receptor binding site bringing relevant
information for the development of novel/derivative agents with atypical
profile.
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