Cheminformatic Identification of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) Inhibitors: A Comparative Study of SMILES-Based Supervised Machine Learning Models.

Background: Tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs damages in DNA induced by abortive topoisomerase 1 activity; however, maintenance of genetic integrity may sustain cellular division of neoplastic cells. It follows that Tdp1-targeting chemical inhibitors could synergize well with existing chemotherapy drugs to deny cancer growth; therefore, identification of Tdp1 inhibitors may advance precision medicine in oncology.

Objective: Current computational research efforts focus primarily on molecular docking simulations, though datasets involving three-dimensional molecular structures are often hard to curate and computationally expensive to store and process. We propose the use of simplified molecular input line entry system (SMILES) chemical representations to train supervised machine learning (ML) models, aiming to predict potential Tdp1 inhibitors.

Methods: An open-sourced consensus dataset containing the inhibitory activity of numerous chemicals against Tdp1 was obtained from Kaggle. Various ML algorithms were trained, ranging from simple algorithms to ensemble methods and deep neural networks. For algorithms requiring numerical data, SMILES were converted to chemical descriptors using RDKit, an open-sourced Python cheminformatics library.

Results: Out of 13 optimized ML models with rigorously tuned hyperparameters, the random forest model gave the best results, yielding a receiver operating characteristics-area under curve of 0.7421, testing accuracy of 0.6815, sensitivity of 0.6444, specificity of 0.7156, precision of 0.6753, and F1 score of 0.6595.

Conclusions: Ensemble methods, especially the bootstrap aggregation mechanism adopted by random forest, outperformed other ML algorithms in classifying Tdp1 inhibitors from non-inhibitors using SMILES. The discovery of Tdp1 inhibitors could unlock more treatment regimens for cancer patients, allowing for therapies tailored to the patient's condition.