Proteochemometric mapping of the interaction of organic compounds with melanocortin receptor subtypes
Proteochemometric mapping of the interaction of organic compounds with melanocortin receptor subtypes
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DOI：
10.1124/mol.104.002857
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发表时间：
2005-01-01
影响因子：
3.6
通讯作者：
Wikberg, JES
中科院分区：
文献类型：
--
作者：
Lapinsh, M;Veiksina, S;Wikberg, JES
蛋白质化学计量学应用于分析有机化合物与野生型和嵌合型黑素皮质素受体的结合。基于统计分子设计设计了13个嵌合黑素皮质素受体；每个嵌合体包含三个mc1,3 -5受体的部分。测定了18种化合物与这些嵌合型黑素皮质素受体和4种野生型黑素皮质素受体的结合亲和力。其中14个化合物的数据与化合物的物理化学和结构描述符、受体序列的二元描述符以及来自配体和受体描述符的交叉项相关，以获得蛋白质化学计量模型（相关性使用偏最小二乘投影到潜在结构；PLS）。拟合良好的数学模型（R-2 = 0.92），预测能力高（Q(2) = 0.79）。为了进一步验证该模型，估计了配体（Q(2)lig = 0.68）和受体（Q(2)rec = 0.76）的预测能力。此外，利用蛋白化学模型中未包含的另外四种化合物的外部预测数据，对模型进行了验证；分析得出Q(2)ext = 0.73。利用PLS系数对结果的解释揭示了有机化合物的特定性质对其对黑素皮质素受体的亲和力的影响。还建立了黑素皮质素受体的三维模型，并将受体跨膜腔内氨基酸的理化性质与PLS建模结果相关联。估计了特定氨基酸对有机化合物选择性结合的重要性，并用于概述黑素皮质素受体中的配体识别位点。
Proteochemometrics was applied in the analysis of the binding of organic compounds to wild-type and chimeric melanocortin receptors. Thirteen chimeric melanocortin receptors were designed based on statistical molecular design; each chimera contained parts from three of the MC1,3-5 receptors. The binding affinities of 18 compounds were determined for these chimeric melanocortin receptors and the four wild-type melanocortin receptors. The data for 14 of these compounds were correlated to the physicochemical and structural descriptors of compounds, binary descriptors of receptor sequences, and cross-terms derived from ligand and receptor descriptors to obtain a proteochemometric model ( correlation was performed using partial least-squares projections to latent structures; PLS). A well fitted mathematical model (R-2 = 0.92) with high predictive ability (Q(2) = 0.79) was obtained. In a further validation of the model, the predictive ability for ligands (Q(2)lig = 0.68) and receptors (Q(2)rec = 0.76) was estimated. The model was moreover validated by external prediction by using the data for the four additional compounds that had not at all been included in the proteochemometric model; the analysis yielded a Q(2)ext = 0.73. An interpretation of the results using PLS coefficients revealed the influence of particular properties of organic compounds on their affinity to melanocortin receptors. Three-dimensional models of melanocortin receptors were also created, and physicochemical properties of the amino acids inside the receptors' transmembrane cavity were correlated to the PLS modeling results. The importance of particular amino acids for selective binding of organic compounds was estimated and used to outline the ligand recognition site in the melanocortin receptors.