Zanatta Geancarlo, Della Flora Nunes Gustavo, Bezerra Eveline M, da Costa Roner F, Martins Alice, Caetano Ewerton W S, Freire Valder N, Gottfried Carmem
Department of Biochemistry, Federal University of Rio Grande do Sul , 90035-003 Porto Alegre, RS Brazil.
Post-graduate Program in Pharmaceutical Sciences, Pharmacy Faculty, Federal University of Ceará , 60430-372 Fortaleza, CE Brazil.
ACS Chem Neurosci. 2016 Oct 19;7(10):1331-1347. doi: 10.1021/acschemneuro.6b00074. Epub 2016 Aug 5.
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.
利培酮是一种非典型抗精神病药物，用于治疗精神分裂症以及与自闭症谱系障碍（ASD）相关的易怒症状。其主要作用机制是阻断D2样受体，作用于精神分裂症的阳性和阴性症状，在对应低/中度D2占据率的剂量下，锥体外系症状（EPS）风险较小。副作用发生率的降低可能与其在黑质纹状体区域从D2受体快速解离有关，从而使多巴胺信号通路得以恢复。我们使用利培酮和D3受体晶体学数据进行了对接实验，结果表明利培酮在结合口袋处可能有两种不同的取向。取向1更靠近结合位点的开口，6-氟-1,2-苯并恶唑片段朝向D3受体裂隙的底部，而取向2在结合口袋内部更深，相同片段朝向受体表面。为了揭示这两种结合取向的影响，我们在密度泛函理论形式体系内以及共轭帽分子分级框架下进行了经典分子动力学和量子生物化学计算。量子力学/分子力学表明，考虑到Glu90的贡献，取向2在能量上比取向1略稳定，主要贡献来自残基Asp110。位于结合位点开口处的残基Glu90，与取向1的距离比与取向2更近，这表明它可能通过与利培酮的吸引相互作用在稳定性方面起关键作用。因此，尽管取向1和取向2都可能发生，但我们认为取向1的出现可能有助于降低服用利培酮患者的副作用，这是通过快速解离机制减少黑质纹状体区域多巴胺受体占据率实现的。非典型效应可能简单地通过在结合位点空间阻碍取向1延迟D3R完全阻断，或者通过有效阻断后取向1快速解离来获得。虽然这项工作中提出的分子解释为利培酮治疗期间观察到的锥体外系症状减少的潜在分子机制提供了一些线索，但为了评估这两种取向在受体激活/抑制过程中的影响，还需要进一步研究。总之，这些数据突出了多巴胺受体结合位点的重要热点，为开发具有非典型特征的新型/衍生药物提供了相关信息。
