The local minima method (LMM) of pharmacophore determination: A protocol for predicting the bioactive conformation of small, conformationally flexible molecules
The local minima method (LMM) of pharmacophore determination: A protocol for predicting the bioactive conformation of small, conformationally flexible molecules
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DOI：
10.1021/ci980404z
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发表时间：
1998-11-01
期刊：
影响因子：
--
通讯作者：
Knittel, JJ
中科院分区：
文献类型：
--
作者：
Demeter, DA;Weintraub, HJR;Knittel, JJ
软件已开发的势能面分析和局部极小值，药效团测定的方法。(1)LMM是严格的和系统的，并采用多个构象，这是局部极小的势能面af数据集中的每个化合物。它从一组假定的药效团元素中产生一系列可能的药效团。然后通过对每一个进行比较分子场分析（CoMFA）来确定最佳药效团。药效团产生最自洽模型的模型被认为是最好的。气相势能面上的局部极小值被证明是一个合理的接近蛋白质结合构象，这些构象可以通过系统的构象搜索，然后最小化的局部极小值。LMM用于开发多巴胺β-羟化酶（DBH）抑制剂的3D-QSAR模型，该模型具有高度预测性（预测R-2 = 0.71，预测标准误差= 0.41）。该模型预测，苯基和噻吩系列的抑制剂作为生物电子等排体。在模型中覆盖的化合物的检查表明在DBH活性位点中可能存在氢键受体。三个酪氨酸残基标记的机制为基础的抑制剂可能作为受体，因此代表了良好的候选人定点突变研究。
Software has been developed for potential energy surface analysis and the local minima,method of pharmacophore determination.(1) LMM is rigorous and systematic and employs multiple conformations which are the local minima from the potential energy surface af each compound in the data set. It produces a series of possible pharmacophores from a postulated set of pharmacophore elements. The best pharmacophore is then determined by performing a comparative molecular field analysis (CoMFA) on each one. The pharmacophore. which produces the most self-consistent model is deemed the best. Local minima on the gas-phase potential energy surface are shown to be a reasonably close-approximation to protein bound conformations, and these conformations can be found through systematic conformational searches followed by minimization of the local minima. LMM was used to develop a 3D-QSAR model for dopamine beta-hydroxylase (DBH) inhibitors which was highly predictive (predictive R-2 = 0.71 and standard error of predictions = 0.41). The model predicted that the phenyl and thienyl series of inhibitors were acting as bioisosteres. Examination of compounds overlayed in the model indicated a possible hydrogen bond acceptor in the DBH active site. Three tyrosine residues previously labeled by mechanism based inhibitors may be acting as the acceptor and therefore represent excellent candidates for site-directed mutagenesis studies.