Timmers Luis Fernando Saraiva Macedo, Caceres Rafael Andrade, Vivan Ana Luiza, Gava Lisandra Marques, Dias Raquel, Ducati Rodrigo Gay, Basso Luiz Augusto, Santos Diogenes Santiago, de Azevedo Walter Filgueira
Faculdade de Biociências, Laboratório de Bioquímica Estrutural, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Arch Biochem Biophys. 2008 Nov 1;479(1):28-38. doi: 10.1016/j.abb.2008.08.015. Epub 2008 Aug 30.
Human purine nucleoside phosphorylase (HsPNP) is a target for inhibitor development aiming at T-cell immune response modulation. In this work, we report the development of a new set of empirical scoring functions and its application to evaluate binding affinities and docking results. To test these new functions, we solved the structure of HsPNP and 2-mercapto-4(3H)-quinazolinone (HsPNP:MQU) binary complex at 2.7A resolution using synchrotron radiation, and used these functions to predict ligand position obtained in docking simulations. We also employed molecular dynamics simulations to analyze HsPNP in two conditions, as apoenzyme and in the binary complex form, in order to assess the structural features responsible for stability. Analysis of the structural differences between systems provides explanation for inhibitor binding. The use of these scoring functions to evaluate binding affinities and molecular docking results may be used to guide future efforts on virtual screening focused on HsPNP.
人类嘌呤核苷磷酸化酶（HsPNP）是旨在调节T细胞免疫反应的抑制剂开发的一个靶点。在这项工作中，我们报告了一组新的经验评分函数的开发及其在评估结合亲和力和对接结果中的应用。为了测试这些新函数，我们使用同步辐射以2.7埃的分辨率解析了HsPNP与2-巯基-4（3H）-喹唑啉酮（HsPNP:MQU）二元复合物的结构，并使用这些函数预测对接模拟中获得的配体位置。我们还采用分子动力学模拟来分析处于两种状态的HsPNP，即脱辅基酶状态和二元复合物形式，以评估负责稳定性的结构特征。对系统间结构差异的分析为抑制剂结合提供了解释。使用这些评分函数来评估结合亲和力和分子对接结果可用于指导未来针对HsPNP的虚拟筛选工作。
