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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >The signaling pathway of dopamine D2 receptor (D2R) activation using normal mode analysis (NMA) and the construction of pharmacophore models for D2R ligands
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The signaling pathway of dopamine D2 receptor (D2R) activation using normal mode analysis (NMA) and the construction of pharmacophore models for D2R ligands

机译：多巴胺D2受体（D2R）激活的信号通路使用正常模式分析（NMA）和D2R配体的药物模型构建

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摘要

G-protein-coupled receptors (GPCRs) are targets of more than 30% of marketed drugs. Investigation on the GPCRs may shed light on upcoming drug design studies. In the present study, we performed a combination of receptor- and ligand-based analysis targeting the dopamine D2 receptor (D2R). The signaling pathway of D2R activation and the construction of universal pharmacophore models for D2R ligands were also studied. The key amino acids, which contributed to the regular activation of the D2R, were in detail investigated by means of normal mode analysis (NMA). A derived cross-correlation matrix provided us an understanding of the degree of pair residue correlations. Although negative correlations were not observed in the case of the inactive D2R state, a high degree of correlation appeared between the residues in the active state. NMA results showed that the cytoplasmic side of the TM5 plays a significant role in promoting of residue-residue correlations in the active state of D2R. Tracing motions of the amino acids Arg219, Arg220, Val223, Asn224, Lys226, and Ser228 in the position of the TM5 are found to be critical in signal transduction. Complementing the receptor-based modeling, ligand-based modeling was also performed using known D2R ligands. The top-scored pharmacophore models were found as 5-sited (AADPR.671, AADRR.1398, AAPRR.3900, and ADHRR.2864) hypotheses from PHASE modeling from a pool consisting of more than 100 initial candidates. The constructed models using 38 D2R ligands (in the training set) were validated with 15 additional test set compounds. The resulting model correctly predicted the pIC(50) values of an additional test set compounds as true unknowns.
机译：G蛋白偶联受体（GPCR）是超过30％的销售药物的目标。对GPCR的调查可以揭示即将到来的药物设计研究。在本研究中，我们进行了靶向多巴胺D2受体（D2R）的受体和配体的分析的组合。还研究了D2R激活的信号通路和D2R配体的通用药物模型的构建。通过正常模式分析（NMA）详细研究了有助于定期激活D2R的关键氨基酸。衍生的互相关矩阵为我们提供了对对残留物相关的程度的理解。尽管在非活动D2R状态的情况下未观察到负相关，但在活性状态下残留物之间出现高度相关性。 NMA结果表明，TM5的细胞质侧在促进D2R的活性状态下促进残留物残留相关性具有重要作用。发现TM5位置中氨基酸arg219，arg220，Val223，AsN224，Lys226和Ser228的追踪运动在信号转导中至关重要。补充基于受体的建模，也使用已知的D2R配体进行配体的建模。从池中的阶段建模的池中的池模型中发现了最额定的药效线模型（AADPR.671，AADRR.1398，AAPRR.3900和ADHRR.2864）。使用38 D2R配体（在训练集中）的构建模型用15个另外的试验组化合物进行了验证。结果模型正确预测了另外的测试集化合物的PIC（50）值作为真实未知。

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