4D-QSAR范式:应用于一组新的非肽类HIV蛋白酶抑制剂

O. Santos-Filho, A. Hopfinger
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引用次数: 15

摘要

D-QSAR分析将药效团,一致性和对齐自由纳入到3D-QSAR模型的开发中,通过执行集成平均,第四维∫来训练结构-活性数据集。进行4D-QSAR分析所需的数据包括一组化合物,通常是类似物,以及它们在普通筛选/分析中测量的生物活性。4D-QSAR方法可应用于受体依赖性(RD)和受体非依赖性(RI)问题。在第一种方案中,受体(分子靶标,通常是酶)的几何形状是可用的。相反,在第二种方案中,受体的几何形状不是可用于执行分析的数据的一部分。4D-QSAR分析中的描述符是由构象和排列空间采样实现的训练集中组成每个分子的原子的晶格网格单元(空间)占用度量。这些网格细胞占用描述符(GCODs)是为许多不同的原子类型生成的,即相互作用的药效因子(IPEs)。在构建用于模型开发的试用描述符池时,非gcod描述符也可以包含在gcod集合中。4D-QSAR分析的基本思想是,一组配体之间的活性差异与它们相对于IPEs的分子形状的玻尔兹曼平均空间分布的差异有关。采用遗传算法(GA)优化和偏最小二乘(PLS)回归相结合的方案生成和评估3D-QSAR模型。假设训练集中的每个化合物都有一个单一的™活性构象,当与最佳排列相结合时,可用于其他分子设计应用,包括其他3D-QSAR方法。4D- QSAR模型还可以作为虚拟屏幕用于处理真实和/或虚拟配体库。本文详细介绍了4D-QSAR模式。此外,我们报告了(RI) 4D-QSAR形式在一组新型非肽类HIV蛋白酶抑制剂中的应用。生成的4D-QSAR模型是稳健的,并提供了关于类似物的可能作用机制的见解,以及关于新的合成路线的提示。此外,这些模型可以作为未来受体依赖性抗hiv药物设计的起点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The 4D-QSAR Paradigm: Application to a Novel Set of Non-peptidic HIV Protease Inhibitors
D-QSAR analysis incorporates pharmacophore, confor- mational and alignment freedom into the development of 3D-QSAR models for training sets of structure-activity data by performing ensemble averaging, the fourth ™di- mension∫. The data required to perform 4D-QSAR analysis includes a training set of compounds, usually analogs, and their measured biological activities in a common screen/assay. The 4D-QSAR approach can be applied to both receptor-dependent (RD) and receptor- independent (RI) problems. In the first scheme, the geometry of the receptor (molecular target, usually an enzyme) is available. In contrast, in the second scheme the geometry of the receptor is not part of the data available to perform the analysis. The descriptors in 4D-QSAR analysis are lattice grid cell (spatial) occupancy measures of atoms composing each molecule in the training set realized from the sampling of conformational and align- ment spaces. These grid cell occupancy descriptors (GCODs) are generated for a number of different atom types, the interaction pharmacophoric elements (IPEs). Non-GCOD descriptors can also be included with the set of GCODs in building the trial descriptor pool for model development. The idea underlying 4D-QSAR analysis is that the differences in activity among a set of ligands are related to differences in their Boltzmann average spatial distribution of molecular shape with respect to the IPEs. The 3D-QSAR models are generated and evaluated by a scheme that combines a genetic algorithm (GA) optimi- zation with partial least-squares (PLS) regression. A single ™active∫ conformation is postulated for each compound in the training set, which, when combined with the optimal alignment, can be used in additional molecular design applications, including other 3D-QSAR methods. The 4D- QSAR models can also be used as virtual screens in the processing of real and/or virtual ligand libraries. In this paper the 4D-QSAR paradigm is given in detail. More- over, we report the application of the (RI) 4D-QSAR formalism to a set of novel nonpeptidic HIV protease inhibitors. The 4D-QSAR models generated are robust and provide insight regarding the probable mechanism of action of the analogs, as well as hints concerning new synthetic routes. Furthermore, these models can be used as a starting point for future receptor-dependent anti-HIV drug design.
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