Classification of FLT3 inhibitors and SAR analysis by machine learning methods.

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase, which is an important target for anti-cancer therapy. In this work, we conducted a structure-activity relationship (SAR) study on 3867 FLT3 inhibitors we collected. MACCS fingerprints, ECFP4 fingerprints, and TT fingerprints were used to represent the inhibitors in the dataset. A total of 36 classification models were built based on support vector machine (SVM), random forest (RF), eXtreme Gradient Boosting (XGBoost), and deep neural networks (DNN) algorithms. Model 3D_3 built by deep neural networks (DNN) and TT fingerprints performed best on the test set with the highest prediction accuracy of 85.83% and Matthews correlation coefficient (MCC) of 0.72 and also performed well on the external test set. In addition, we clustered 3867 inhibitors into 11 subsets by the K-Means algorithm to figure out the structural characteristics of the reported FLT3 inhibitors. Finally, we analyzed the SAR of FLT3 inhibitors by RF algorithm based on ECFP4 fingerprints. The results showed that 2-aminopyrimidine, 1-ethylpiperidine,2,4-bis(methylamino)pyrimidine, amino-aromatic heterocycle, [(2E)-but-2-enyl]dimethylamine, but-2-enyl, and alkynyl were typical fragments among highly active inhibitors. Besides, three scaffolds in Subset_A (Subset 4), Subset_B, and Subset_C showed a significant relationship to inhibition activity targeting FLT3.