Two Binding Geometries for Risperidone in Dopamine D3 Receptors: Insights on the Fast-Off Mechanism through Docking, Quantum Biochemistry, and Molecular Dynamics Simulations.

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 1 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.