One molecular fingerprint to rule them all: drugs, biomolecules, and the metabolome
One molecular fingerprint to rule them all: drugs, biomolecules, and the metabolome
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DOI：
10.1186/s13321-020-00445-4
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发表时间：
2020-06-12
影响因子：
8.6
通讯作者：
Reymond, Jean-Louis
中科院分区：
文献类型：
--
作者：
Capecchi, Alice;Probst, Daniel;Reymond, Jean-Louis
背景分子指纹图谱是化学信息学中虚拟筛选和化学空间定位的重要工具。在不同类型的指纹图谱中，亚结构指纹图谱对小分子（如药物）表现最好，而原子对指纹图谱对大分子（如肽）表现最好。然而，没有可用的指纹在这两类分子上实现良好的性能。结果结合亚结构和原子对的概念，设计了一种适用于小分子和大分子的新指纹图谱。我们的探索产生了一种新的指纹，称为MinHash原子对指纹，直径高达四个键（MAP 4）。在这个指纹中，原子对中每个原子周围的半径为r = 1和r = 2的圆形子结构被写为两对SMILES，每对与分离两个中心原子的拓扑距离相结合。对这些所谓的原子对分子瓦片进行哈希，并对所得哈希集进行MinHashed以形成MAP 4指纹。在将Riniker和Landrum小分子基准与从乱序或点突变类似物中回收BLAST类似物的肽基准组合的扩展基准上，MAP4显著优于所有其他指纹。MAP4还为DrugBank、ChEMBL、SwissProt和人类代谢组数据库（HMBD）等不同数据库生成组织良好的化学空间树图（TMAP），并区分HMBD中的所有代谢物，其中超过70%的代谢物使用子结构指纹无法与其最近邻区分开。结论MAP4是一种新的分子指纹图谱，适用于药物、生物分子和代谢物组，可作为一种通用的指纹图谱来描述和寻找化学空间。源代码可在和交互式MAP4相似性搜索工具和TMAP各种数据库访问。
Background Molecular fingerprints are essential cheminformatics tools for virtual screening and mapping chemical space. Among the different types of fingerprints, substructure fingerprints perform best for small molecules such as drugs, while atom-pair fingerprints are preferable for large molecules such as peptides. However, no available fingerprint achieves good performance on both classes of molecules. Results Here we set out to design a new fingerprint suitable for both small and large molecules by combining substructure and atom-pair concepts. Our quest resulted in a new fingerprint called MinHashed atom-pair fingerprint up to a diameter of four bonds (MAP4). In this fingerprint the circular substructures with radii ofr = 1 andr = 2 bonds around each atom in an atom-pair are written as two pairs of SMILES, each pair being combined with the topological distance separating the two central atoms. These so-called atom-pair molecular shingles are hashed, and the resulting set of hashes is MinHashed to form the MAP4 fingerprint. MAP4 significantly outperforms all other fingerprints on an extended benchmark that combines the Riniker and Landrum small molecule benchmark with a peptide benchmark recovering BLAST analogs from either scrambled or point mutation analogs. MAP4 furthermore produces well-organized chemical space tree-maps (TMAPs) for databases as diverse as DrugBank, ChEMBL, SwissProt and the Human Metabolome Database (HMBD), and differentiates between all metabolites in HMBD, over 70% of which are indistinguishable from their nearest neighbor using substructure fingerprints. Conclusion MAP4 is a new molecular fingerprint suitable for drugs, biomolecules, and the metabolome and can be adopted as a universal fingerprint to describe and search chemical space. The source code is available atand interactive MAP4 similarity search tools and TMAPs for various databases are accessible atand.