1,2,4-oxadiazole类非季胺肟胆碱酯酶重活化剂的CoMFA研究

The CoMFA study on nonquaternary cholinesterase reactivators:1,2,4-oxadiazole derivatives

应用比较分子力场法(CoMFA)研究一系列1,2,4-oxadiazole非季胺肟类乙酰胆碱酯酶(AChE)重活化剂的三维定量构效关系。以肟基(-c=N-OH)部分进行有效分子重叠,得到两个不同种属的CoMFA 摸型的交叉验证系数q^2>0.5,具有一定预测能力及合理性。其中,该类化合物在复活人类体外EPMP 抑制的AChE 活性的3D-QSAR 模型中q^2=0.530,非交叉验证模型相关系数r^2=0.992,标准偏差SE=0.198,F=196.7;并依据此模型设计、预测了3个理论上具有较高活性的化合物。

To explore a better reactivator which can afford significant advantages over conventional quaternary reactivators oforganophosphate-inhibited enzyme,the advanced 3D-QSAR method-CoMFA(comparative molecular field analysis)wasused to study 1,2,4-oxadiazole derivatives-a class of non-quaternary cholinesterase reactivators.The study showed thatthe molecule superposing based on the common substructure-oxime moiety(-C=N-OH)was effective,and it leaded totwo rational CoMFA models for two different spieces(human and eel).The Crossvalidated coefficient q^2 of both modelswere more than 0.5,so they could be used to predict biological activities of other derivatives.Especially,the q^2 of the mod-el for the human AChE in vitro reached 0.530;the non-crossvalidated coeffecient r^2 was up to 0.992;standard deviationwas 0.198;and F=196.7.Three new compounds were designed based on the plot of CoMFA coefficient,which were pre-dicted to be high reactivity for EPMP inhibited human AChE in vitro.It(?) helpful to the next synthesize work to find a newreactivator with higher efficacy.