Binding free energy calculations and biological testing of novel thiobarbiturates as inhibitors of the human NAD+ dependent histone deacetylase Sirt2
Binding free energy calculations and biological testing of novel thiobarbiturates as inhibitors of the human NAD+ dependent histone deacetylase Sirt2
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DOI：
10.1039/c1md00214g
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Sippl, Wolfgang
中科院分区：
文献类型：
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作者：
Uciechowska, Urszula;Schemies, Joerg;Sippl, Wolfgang
进行多步虚拟筛选以鉴定人NAD（+）依赖性脱乙酰酶sirtuin 2（Sirt 2）的抑制剂。分子力学泊松-玻尔兹曼表面积（MM-PB/SA）和线性相互作用能（LIE）的计算进行了训练集的10个最近确定的Sirt 2抑制剂从我们的实验室。对接分数没有重现相对结合自由能估计从体外数据，而LIE和MM-PB/SA数据被发现是在良好的协议与实验数据的10个抑制剂。这两种结合自由能方法都成功地预测了14种新的硫代巴比妥类药物的活性，并导致Sirt 2抑制剂的活性比训练集的活性高10倍。通过对接和基于MD的结合自由能计算相结合获得的数据显示了该方法预测新型沉默调节蛋白抑制剂结合自由能的性能。
A multi-step virtual screening was carried out in order to identify inhibitors of human NAD(+)- dependent deacetylase sirtuin 2 (Sirt2). Molecular mechanics Poisson-Boltzmann surface area (MM-PB/SA) and linear interaction energy (LIE) calculations were carried out on a training set of ten recently identified Sirt2 inhibitors from our laboratory. The docking scores did not reproduce the relative binding free energies estimated from the in vitro data, while the LIE and the MM-PB/SA data were found to be in good agreement with the experimental data for the ten inhibitors. Both binding free energy methods were successful in predicting the activity of 14 novel identified thiobarbiturates and led to Sirt2 inhibitors that are ten-fold more active than those from the training set. The provided data obtained by the combination of docking and MD-based binding free energy calculations show the performance of the approach for predicting the binding free energy of novel sirtuin inhibitors.