药效团
化学
公共化学
虚拟筛选
化学信息学
计算机科学
化学空间
拓扑(电路)
组合化学
化学
药物发现
数学
生物信息学
计算生物学
计算化学
立体化学
组合数学
生物
作者
Hiroshi Nakano,Tomoyuki Miyao,Swarit Jasial,Kimito Funatsu
标识
DOI:10.1021/acs.jcim.1c00409
摘要
The aim of scaffold hopping (SH) is to find compounds consisting of different scaffolds from those in already known active compounds, giving an opportunity for unexplored regions of chemical space. We previously demonstrated the usefulness of pharmacophore graphs (PhGs) for this purpose through proof-of-concept virtual screening experiments. PhGs consist of nodes and edges corresponding to pharmacophoric features (PFs) and their topological distances. Although PhGs were effective in SH, they are hard to interpret as they are complete graphs. Herein, we introduce an intuitive representation of a molecule, termed as sparse pharmacophore graphs (SPhG) by keeping the topological distances among PFs as much as possible while reducing the number of edges in the graphs. Several benchmark calculations quantitatively confirmed the sparseness of the graphs and the preservation of topological distances among pharmacophoric points. As proof-of-concept applications, virtual screening (VS) trials for SH were conducted using active and inactive compounds from ChEMBL and PubChem databases for three biological targets: thrombin, tyrosine kinase ABL1, and κ-opioid receptor. The performances of VS were comparable with using fully connected PhGs. Furthermore, highly ranked SPhGs were interpretable for the three biological targets, in particular for thrombin, for which selected SPhGs were in agreement with the structure-based interpretation.
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