Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
J Mol Model. 2012 May;18(5):1701-11. doi: 10.1007/s00894-011-1187-0. Epub 2011 Aug 9.
Pteridine reductase is a promising target for development of novel therapeutic agents against Trypanosomatid parasites. A 3D-QSAR pharmacophore hypothesis has been generated for a series of L. major pteridine reductase inhibitors using Catalyst/HypoGen algorithm for identification of the chemical features that are responsible for the inhibitory activity. Four pharmacophore features, namely: two H-bond donors (D), one Hydrophobic aromatic (H) and one Ring aromatic (R) have been identified as key features involved in inhibitor-PTR1 interaction. These features are able to predict the activity of external test set of pteridine reductase inhibitors with a correlation coefficient (r) of 0.80. Based on the analysis of the best hypotheses, some potent Pteridine reductase inhibitors were screened out and predicted with anti-PTR1 activity. It turned out that the newly identified inhibitory molecules are at least 300 fold more potent than the current crop of existing inhibitors. Overall the current SAR study is an effort for elucidating quantitative structure-activity relationship for the PTR1 inhibitors. The results from the combined 3D-QSAR modeling and molecular docking approach have led to the prediction of new potent inhibitory scaffolds.
蝶啶还原酶是开发新型抗锥虫寄生虫治疗药物的有前途的靶标。使用 Catalyst/HypoGen 算法为一系列 L. major 蝶啶还原酶抑制剂生成了 3D-QSAR 药效团假设，以确定负责抑制活性的化学特征。已经确定了四个药效团特征，即：两个氢键供体（D），一个疏水芳基（H）和一个环芳基（R），它们是参与抑制剂-PTR1 相互作用的关键特征。这些特征能够以 0.80 的相关系数（r）预测蝶啶还原酶抑制剂的外部测试集的活性。基于最佳假设的分析，筛选出一些有效的蝶啶还原酶抑制剂，并预测具有抗-PTR1 活性。事实证明，新鉴定的抑制分子比当前现有的抑制剂至少强 300 倍。总体而言，目前的 SAR 研究是阐明 PTR1 抑制剂的定量构效关系的努力。结合 3D-QSAR 建模和分子对接方法的结果导致了新的有效抑制支架的预测。
