A novel alignment-free molecular descriptor called xMaP (flexible MaP descriptor) is introduced. The descriptor is the advancement of the previously published translationally and rotationally invariant three-dimensional (3D) descriptor MaP (mapping property distributions onto the molecular surface) to the fourth dimension (4D). In addition to MaP, xMaP is independent of the chosen starting conformation of the encoded molecules and is therefore entirely alignment-free. This is achieved by using ensembles of conformers, which are generated by conformational searches. This step of the procedure is similar to Hopfinger’s 4D quantitative structure–activity relationship (QSAR). A five-step procedure is used to compute the xMaP descriptor. First, a conformational search for each molecule is carried out. Next, for each of the conformers an approximation to the molecular surface with equally distributed surface points is computed. Third, molecular properties are projected onto this surface. Fourth, areas of identical properties are clustered to so-called patches. Fifth, the spatial distribution of the patches is converted into an alignment-free descriptor that is based on the entire conformer ensemble. The resulting descriptor can be interpreted by superimposing the most important descriptor variables and the molecules of the data set. The most important descriptor variables are identified with chemometric regression tools. The novel descriptor was applied to several benchmark data sets and was compared to other descriptors and QSAR techniques comprising a binary fingerprint, a topological pharmacophore descriptor (Cats2D), and the field-based 3D-QSAR technique GRID/PLS which is alignment-dependent. The use of conformer ensembles renders xMaP very robust. It turns out that xMaP performs very well on (almost) all data sets and that the statistical results are comparable to GRID/PLS. In addition to that, xMaP can also be used to efficiently visualize the derived quantitative structure–activity relationships.

中文翻译：

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xMaP-基于分子表面性质和构象整合体的可解释的无取向四维定量构效关系技术

介绍了一种新颖的无比对分子描述符，称为xMaP（柔性MaP描述符）。描述符是先前发布的平移和旋转不变三维（3D）描述符MaP（分子表面上的映射特性分布）到第四维（4D）的改进。除MaP之外，xMaP不受编码分子选择的起始构象的影响，因此是完全无比对的。这是通过使用构象搜索的合体而实现的。该过程的这一步骤类似于Hopfinger的4D定量结构-活性关系（QSAR）。使用五步过程来计算xMaP描述符。首先，对每个分子进行构象搜索。下一个，对于每个构象异构体，将计算出具有均等分布的表面点的分子表面的近似值。第三，将分子特性投射到该表面上。第四，具有相同属性的区域聚集到所谓的补丁中。第五，将补丁的空间分布转换为基于整个构象体集合的无对齐描述符。可以通过叠加最重要的描述符变量和数据集的分子来解释生成的描述符。最重要的描述符变量是使用化学计量回归工具确定的。将该新型描述符应用于多个基准数据集，并与其他描述符和QSAR技术进行了比较，包括二进制指纹，拓扑药效团描述符（Cats2D），以及基于对准的基于现场的3D-QSAR技术GRID / PLS。构象合奏的使用使xMaP非常健壮。事实证明，xMaP在（几乎）所有数据集上都表现出色，并且统计结果与GRID / PLS相当。除此之外，xMaP还可以用于有效地可视化导出的定量结构与活性之间的关系。