A Simple Machine Learning-Based Quantitative Structure–Activity Relationship Model for Predicting pIC50 Inhibition Values of FLT3 Tyrosine Kinase

Background/Objectives: Acute myeloid leukemia (AML) presents significant therapeutic challenges, particularly in cases driven by mutations in the FLT3 tyrosine kinase. This study aimed to develop a robust and user-friendly machine learning-based quantitative structure–activity relationship (QSAR) model to predict the inhibitory potency (pIC50 values) of FLT3 inhibitors, addressing the limitations of previous models in dataset size, diversity, and predictive accuracy. Methods: Using a dataset which was 14 times larger than those employed in prior studies (1350 compounds with 1269 molecular descriptors), we trained a random forest regressor, chosen due to its superior predictive performance and resistance to overfitting. Rigorous internal validation via leave-one-out and 10-fold cross-validation yielded Q2 values of 0.926 and 0.922, respectively, while external validation on 270 independent compounds resulted in an R2 value of 0.941 with a standard deviation of 0.237. Results: Key molecular descriptors influencing the inhibitor potency were identified, thereby improving the interpretability of structural requirements. Additionally, a user-friendly computational tool was developed to enable rapid prediction of pIC50 values and facilitate ligand-based virtual screening, leading to the identification of promising FLT3 inhibitors. Conclusions: These results represent a significant advancement in the field of FLT3 inhibitor discovery, offering a reliable, practical, and efficient approach for early-stage drug development, potentially accelerating the creation of targeted therapies for AML.

Project(s)

Fortalecimiento y desarrollo de la investigación biomédica mediante la adquisición de un cluster computacional

Dataset(s)

Dataset - A Simple Machine Learning-Based Quantitative Structure–Activity Relationship Model for Predicting pIC50 Inhibition Values of FLT3 Tyrosine Kinase

Subjects

cd135 antigen

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flt3 tyrosine kinase

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protein tyrosine kinase

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unclassified drug

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acute myeloid leukemia

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article

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computer aided drug design

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data integrity

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drug design

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ic50

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ligand based drug design

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machine learning

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mean absolute error

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quantitative structure activity relation

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random forest

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support vector machine