A 3D model of the human A1 adenosine receptor. An evaluation of the binding free-energy with ligands.

Drug design and discovery Pub Date : 1998-05-01
A M Bianucci, M U Bigi, G Biagi, I Giorgi, O Livi, V Scartoni
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Abstract

A model of A1 adenosine receptor was built on the basis of the prediction of transmembrane helices made by PHDtopology and forcing the rough initial model over the scaffold of the rhodopsin. Only helices were accurately modeled. Several complexes between the model of the A1 receptor and some ligands were built. The binding site was hypothesized on the basis of biochemical experiments (site directed mutagenesis). Ligands were selected so that their Kis range between millimolar to nanomolar. The validation of the model was carried out performing calculations of the binding free energy between ligands and the receptor model. The free energy calculations were accomplished by using the linear free energy approximation method (LIE). We could observe that the trend of the calculated delta delta Gs (differences in binding free energies between the antagonist 2, showing the lowest Ki, and the other antagonists analyzed) agreed with the one obtained from biological data.

人体A1腺苷受体的三维模型。配体结合自由能的评价。
基于PHDtopology对跨膜螺旋的预测,并将粗糙的初始模型强制置于视紫质支架上,建立了A1腺苷受体的模型。只有螺旋被精确建模。在A1受体模型和一些配体之间建立了一些配合物。结合位点是根据生物化学实验(位点定向诱变)假设的。配体的选择使其Kis在毫摩尔到纳摩尔之间。通过计算配体与受体之间的结合自由能,对模型进行了验证。利用线性自由能近似法(LIE)完成了自由能的计算。我们可以观察到,计算出的δ δ g(显示Ki最低的拮抗剂2与所分析的其他拮抗剂之间的结合自由能之差)的趋势与从生物学数据中得到的趋势一致。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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