Dataset Information

StackER: a novel SMILES-based stacked approach for the accelerated and efficient discovery of ERα and ERβ antagonists.

ABSTRACT: The role of estrogen receptors (ERs) in breast cancer is of great importance in both clinical practice and scientific exploration. However, around 15-30% of those affected do not see benefits from the usual treatments owing to the innate resistance mechanisms, while 30-40% will gain resistance through treatments. In order to address this problem and facilitate community-wide efforts, machine learning (ML)-based approaches are considered one of the most cost-effective and large-scale identification methods. Herein, we propose a new SMILES-based stacked approach, termed StackER, for the accelerated and efficient identification of ERα and ERβ inhibitors. In StackER, we first established an up-to-date dataset consisting of 1,996 and 1,207 compounds for ERα and ERβ, respectively. Using the up-to-date dataset, StackER explored a wide range of different SMILES-based feature descriptors and ML algorithms in order to generate probabilistic features (PFs). Finally, the selected PFs derived from the two-step feature selection strategy were used for the development of an efficient stacked model. Both cross-validation and independent tests showed that StackER surpassed several conventional ML classifiers and the existing method in precisely predicting ERα and ERβ inhibitors. Remarkably, StackER achieved MCC values of 0.829-0.847 and 0.712-0.786 in terms of the cross-validation and independent tests, respectively, which were 5.92-8.29 and 1.59-3.45% higher than the existing method. In addition, StackER was applied to determine useful features for being ERα and ERβ inhibitors and identify FDA-approved drugs as potential ERα inhibitors in efforts to facilitate drug repurposing. This innovative stacked method is anticipated to facilitate community-wide efforts in efficiently narrowing down ER inhibitor screening.

SUBMITTER: Schaduangrat N

PROVIDER: S-EPMC10752908 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

StackER: a novel SMILES-based stacked approach for the accelerated and efficient discovery of ERα and ERβ antagonists.

Schaduangrat Nalini N Homdee Nutta N Shoombuatong Watshara W

Scientific reports 20231227 1

The role of estrogen receptors (ERs) in breast cancer is of great importance in both clinical practice and scientific exploration. However, around 15-30% of those affected do not see benefits from the usual treatments owing to the innate resistance mechanisms, while 30-40% will gain resistance through treatments. In order to address this problem and facilitate community-wide efforts, machine learning (ML)-based approaches are considered one of the most cost-effective and large-scale identificati ...[more]

PMID: 38151513

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Project description:Generative deep learning models have emerged as a powerful approach for de novo drug design as they aid researchers in finding new molecules with desired properties. Despite continuous improvements in the field, a subset of the outputs that sequence-based de novo generators produce cannot be progressed due to errors. Here, we propose to fix these invalid outputs post hoc. In similar tasks, transformer models from the field of natural language processing have been shown to be very effective. Therefore, here this type of model was trained to translate invalid Simplified Molecular-Input Line-Entry System (SMILES) into valid representations. The performance of this SMILES corrector was evaluated on four representative methods of de novo generation: a recurrent neural network (RNN), a target-directed RNN, a generative adversarial network (GAN), and a variational autoencoder (VAE). This study has found that the percentage of invalid outputs from these specific generative models ranges between 4 and 89%, with different models having different error-type distributions. Post hoc correction of SMILES was shown to increase model validity. The SMILES corrector trained with one error per input alters 60-90% of invalid generator outputs and fixes 35-80% of them. However, a higher error detection and performance was obtained for transformer models trained with multiple errors per input. In this case, the best model was able to correct 60-95% of invalid generator outputs. Further analysis showed that these fixed molecules are comparable to the correct molecules from the de novo generators based on novelty and similarity. Additionally, the SMILES corrector can be used to expand the amount of interesting new molecules within the targeted chemical space. Introducing different errors into existing molecules yields novel analogs with a uniqueness of 39% and a novelty of approximately 20%. The results of this research demonstrate that SMILES correction is a viable post hoc extension and can enhance the search for better drug candidates.

Dataset Information

StackER: a novel SMILES-based stacked approach for the accelerated and efficient discovery of ERα and ERβ antagonists.

Publications

StackER: a novel SMILES-based stacked approach for the accelerated and efficient discovery of ERα and ERβ antagonists.

Similar Datasets

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