Consensus QSAR Modeling of Phosphor-Containing Chiral ACNE Inhibitors
Consensus QSAR Modeling of Phosphor-Containing Chiral ACNE Inhibitors
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DOI：
10.1002/qsar.200860117
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发表时间：
2009-07-01
期刊：
影响因子：
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通讯作者：
Leszczynski, Jerzy
中科院分区：
文献类型：
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作者：
Kuz'min, Victor E.;Muratov, Eugene N.;Leszczynski, Jerzy
本文采用分层QSAR技术（HiT QSAR）建立了有机磷化合物抑制乙酰胆碱酯酶（ACNE）的一致性QSAR模型。分子结构的单纯形表示（SiRMS）和晶格模型（LM）的QSAR方法已被用于描述符的生成。采用偏最小二乘法（PLS）建立了统计模型。研究了以（R）-和（S）-异构体、外消旋混合物和非手性结构为代表的各种手性有机磷酸酯。成功的共识模型（R-2=0.978）的基础上获得的14个最佳的QSAR模型，使用不同的QSAR方法和训练集的几个水平和方法的分子结构表示（2.5D，双2.5D，和3D）已被用于预测新化合物的痤疮抑制。为了避免偶然相关性，对每个选定的模型执行1000轮Y-加扰。杠杆和椭圆体适用域（DA）方法已被用于额外的预后质量的估计。已经确定了增强和干扰抑制活性的分子片段。结果表明，不对称磷原子的原子独立性和手性环境的立体化学在抑制ACNE中起着重要作用。因此，（R）-异构体的活性总是低于（S）异构体和外消旋体。HiT QSAR被证明是一个强有力的工具，调查活动的立体选择性相互作用，并可用于此类后续研究。
In this article the Hierarchical QSAR technology (HiT QSAR) has been used for consensus QSAR modeling of Acetylcholinesterase (ACNE) inhibition by various organophosphate compounds. Simplex representation of molecular structure (SiRMS) and Lattice model (LM) QSAR approaches have been used for descriptors' generation. Statistical models have been obtained by partial least squares (PLS) method. Various chiral organophosphates represented by their (R)- and (S)-isomers, racemic mixtures and achiral structures have been investigated. Successful consensus model (R-2=0.978) based on fourteen best QSAR models obtained using different QSAR approaches and training sets for several levels and methods of molecular structure representation (2.5D, double 2.5D, and 3D) has been used for the prediction of ACNE inhibition of new compounds. In order to avoid chance correlations 1000 rounds of Y-scrambling were performed for each selected model. Leverage and ellipsoid Applicability domain (DA) approaches have been used for additional estimation of the quality of prognosis. Molecular fragments enhancing and interfering with inhibitory activity have been determined. It was revealed that atom's individuality and stereochemistry of chiral surroundings of the asymmetric atom of phosphorus play a vital role in ACNE inhibition. Thus, (R)-isomers are always less active than the (S) isomers and the racemate. HiT QSAR proves to be a powerful tool for investigation of activity of stereo selective interactions and can be used in such subsequent studies.