Identification of small molecule aggregators from large compound libraries by support vector machines.
Small molecule aggregators non-specifically inhibit multiple unrelated proteins, rendering them therapeutically useless. They frequently appear as false hits and thus need to be eliminated in high-throughput screening campaigns. Computational methods have been explored for identifying aggregators, which have not been tested in screening large compound libraries. We used 1319 aggregators and 128,325 non-aggregators to develop a support vector machines (SVM) aggregator identification model, which was tested by four methods. The first is five fold cross-validation, which showed comparable aggregator and significantly improved non-aggregator identification rates against earlier studies. The second is the independent test of 17 aggregators discovered independently from the training aggregators, 71% of which were correctly identified. The third is retrospective screening of 13M PUBCHEM and 168K MDDR compounds, which predicted 97.9% and 98.7% of the PUBCHEM and MDDR compounds as non-aggregators. The fourth is retrospective screening of 5527 MDDR compounds similar to the known aggregators, 1.14% of which were predicted as aggregators. SVM showed slightly better overall performance against two other machine learning methods based on five fold cross-validation studies of the same settings. Molecular features of aggregation, extracted by a feature selection method, are consistent with published profiles. SVM showed substantial capability in identifying aggregators from large libraries at low false-hit rates.
Rao
Hanbing
H
College of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China.
Li
Zerong
Z
Li
Xiangyuan
X
Ma
Xiaohua
X
Ung
Choongyong
C
Li
Hu
H
Liu
Xianghui
X
Chen
Yuzong
Y
D001185:Artificial Intelligence; D003198:Computer Simulation; D057166:High-Throughput Screening Assays; D015394:Molecular Structure; D054852:Small Molecule Libraries; D012984:Software
D054852:Small Molecule Libraries