Abstract
A structurally diverse dataset of 530 polo-like kinase-1 (PLK1) inhibitors is compiled from the ChEMBL database and studied by means of a conformation-independent quantitative structure-activity relationship (QSAR) approach. A large number (26,761) of molecular descriptors are explored with the main intention of capturing the most relevant structural characteristics affecting the bioactivity. The structural descriptors are derived with different freeware, such as PaDEL, Mold2, and QuBiLs-MAS; such descriptor software complements each other and improves the QSAR results. The best multivariable linear regression models are found with the replacement method variable subset selection technique. The balanced subsets method partitions the dataset into training, validation, and test sets. It is found that the proposed linear QSAR model improves previously reported models by leading to a simpler alternative structure-activity relationship.
Highlights
Polo-like kinases (PLKs) are characterized by a multidomain structure consisting of a highly conserved N-terminal catalytic domain (KD) and a relatively divergent C-terminal polo-box domain (PBD), composed of either one or two polo boxes [1,2]
We resort to the in the present work, we develop a QSARand analysis for searching predictive on a large conformation-independent approach consider constitutional andmodels topological and structurally diverse dataset of
Technique, we obtain balanced subsets with Ntrain = 265, Nval = 133 and Ntest = 132 compounds; in addition, Table S1 denotes the members of val (ˆ) and test (*) sets
Summary
Polo-like kinases (PLKs) are characterized by a multidomain structure consisting of a highly conserved N-terminal catalytic domain (KD) and a relatively divergent C-terminal polo-box domain (PBD), composed of either one or two polo boxes [1,2]. This serine/threonine kinase family is an important regulator of mitotic progression [3]. The PBD is critical to PLK1 localization and function and negatively regulates the kinase activity of the catalytic domain [1]. Inhibitors targeting KD, the so-called ATP-competitive PLK1 inhibitors, have attracted much attention over the last years [6]
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