EGFRisopred: a machine learning-based classification model for identifying isoform-specific inhibitors against EGFR and HER2.

The EGFR kinase pathway is one of the most frequently activated signaling pathways in human cancers. EGFR and HER2 are the two significant members of this pathway, which are attractive drug targets of clinical relevance in lung and breast cancer. Therefore, identifying EGFR- and HER2-specific inhibitors is one of the important challenges in cancer drug discovery. To address this issue, a dataset of 519 compounds having inhibitory activity against both the isoforms, i.e., EGFR and HER2, was collected from the literature and developed a knowledge-based computational classification model for predicting the specificity of a molecule for an isoform (EGFR/HER2) with precision. A total of seventy-two classification models using nine fingerprint types, four classifiers (IBK, NB, SMO and RF) and two different datasets (EGFR and HER2 isoform specific) were developed. It was observed that the models developed using random forest and IBK performed better for EGFR- and HER2-specific datasets, respectively. Scaffold and functional group analysis led to the identification of prevalent core and fragments in each of the datasets. The accuracy of the selected best performing models was also evaluated using the decoy dataset. We have also developed an application EGFRisopred, which integrates the best performing models and permits the user to predict the specificity of a compound as an EGFR-/HER2-specific anticancer agent. It is expected that the tool's availability as a free utility will allow researchers to identify new inhibitors against these targets important in cancer.