Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD 20910, USA.
Eur J Med Chem. 2012 Mar;49:229-38. doi: 10.1016/j.ejmech.2012.01.016. Epub 2012 Jan 21.
We earlier reported an in silico pharmacophore model for reactivation of oximes to tabun-inhibited AChE. Since DFP (diisopropylfluorophosphate) like tabun is a G-agent simulator, we utilized the model as a rational strategy to discover non-oxime reactivators of DFP-inhibited AChE in this study. The phramacophore was used for virtual screening of two commercial databases, Maybridge and ChemNavigator, to identify reactivators which lack the oxime functions. The procedure led us to identify several potent non-oxime compounds that reactivate DFP-inhibited AChE. These non-oxime reactivators contain a nucleophile group in lieu of the oxime moiety in the compound. Five of these novel non-oximes showed Kr values within ten-fold of 2-PAM in an in vitro assay. The pharmacophore model contained a hydrogen bond acceptor, a hydrogen bond donor, and an aromatic ring features distributed in a 3D space. Calculated stereoelectronic properties reported earlier with respect to the location of molecular orbitals and electrostatic potentials were consistent with the model and the newly identified compounds. Down selection of compounds after virtual screening was performed on the basis of fit score to the model, conformational energy, and in silico evaluations for favorable blood-brain barrier (BBB) penetrability, octanol-water partition (log P), and toxicity (rat oral LD(50)) assessments. In vitro reactivation efficacy of the compounds was evaluated in a DFP-inhibited eel acetylcholinesterase assay.
我们之前报道了一种用于肟类化合物重新激活塔崩抑制的乙酰胆碱酯酶的计算药效团模型。由于 DFP（二异丙基氟磷酸酯）类似于塔崩，是一种 G 类模拟物，因此我们在这项研究中利用该模型作为一种合理的策略来发现非肟类化合物，以重新激活 DFP 抑制的乙酰胆碱酯酶。该药效团模型用于虚拟筛选两个商业数据库，即 Maybridge 和 ChemNavigator，以识别缺乏肟功能的再激活剂。该程序使我们确定了几种有效的非肟类化合物，可重新激活 DFP 抑制的乙酰胆碱酯酶。这些非肟类再激活剂含有亲核基团，取代了化合物中肟部分。其中五种新型非肟类化合物在体外测定中，Kr 值在 2-PAM 的十倍范围内。药效团模型包含氢键受体、氢键供体和芳香环特征，分布在三维空间中。早期根据分子轨道和静电势的位置计算出的立体电子性质与模型和新鉴定的化合物一致。虚拟筛选后，根据与模型的拟合得分、构象能以及血脑屏障（BBB）渗透性、辛醇-水分配系数（log P）和毒性（大鼠口服 LD（50））评估等因素，对化合物进行了进一步的筛选。通过在 DFP 抑制的鳗鱼乙酰胆碱酯酶测定中评估化合物的体外再激活效果，对化合物进行了评价。
