Nakano Hiroshi, Miyao Tomoyuki, Swarit Jasial, Funatsu Kimito
Graduate School of Science and Technology, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan.
Data Science Center, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma, Nara 630-0192, Japan.
J Chem Inf Model. 2021 Jul 26;61(7):3348-3360. doi: 10.1021/acs.jcim.1c00409. Epub 2021 Jul 15.
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.
骨架跃迁（SH）的目的是找到与已知活性化合物骨架不同的化合物，从而为化学空间中未探索的区域提供机会。我们之前通过概念验证虚拟筛选实验证明了药效团图（PhGs）在此目的上的有用性。PhGs由与药效特征（PFs）及其拓扑距离相对应的节点和边组成。尽管PhGs在骨架跃迁中有效，但由于它们是完全图，所以难以解释。在此，我们引入一种分子的直观表示，通过尽可能保留PFs之间的拓扑距离同时减少图中的边数，将其称为稀疏药效团图（SPhG）。几个基准计算定量地证实了图的稀疏性以及药效点之间拓扑距离的保留。作为概念验证应用，使用来自ChEMBL和PubChem数据库的活性和非活性化合物针对三个生物靶点：凝血酶、酪氨酸激酶ABL1和κ-阿片受体进行了骨架跃迁的虚拟筛选（VS）试验。VS的性能与使用完全连接的PhGs相当。此外，高度排名的SPhGs对于这三个生物靶点是可解释的，特别是对于凝血酶，所选的SPhGs与基于结构的解释一致。
