TY - JOUR
T1 - Machine Learning Models Identify New Inhibitors for Human OATP1B1
AU - Lane, Thomas R.
AU - Urbina, Fabio
AU - Zhang, Xiaohong
AU - Fye, Margret
AU - Gerlach, Jacob
AU - Wright, Stephen H.
AU - Ekins, Sean
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/11/7
Y1 - 2022/11/7
N2 - The uptake transporter OATP1B1 (SLC01B1) is largely localized to the sinusoidal membrane of hepatocytes and is a known victim of unwanted drug-drug interactions. Computational models are useful for identifying potential substrates and/or inhibitors of clinically relevant transporters. Our goal was to generate OATP1B1 in vitro inhibition data for [3H] estrone-3-sulfate (E3S) transport in CHO cells and use it to build machine learning models to facilitate a comparison of seven different classification models (Deep learning, Adaboosted decision trees, Bernoulli naïve bayes, k-nearest neighbors (knn), random forest, support vector classifier (SVC), logistic regression (lreg), and XGBoost (xgb)] using ECFP6 fingerprints to perform 5-fold, nested cross validation. In addition, we compared models using 3D pharmacophores, simple chemical descriptors alone or plus ECFP6, as well as ECFP4 and ECFP8 fingerprints. Several machine learning algorithms (SVC, lreg, xgb, and knn) had excellent nested cross validation statistics, particularly for accuracy, AUC, and specificity. An external test set containing 207 unique compounds not in the training set demonstrated that at every threshold SVC outperformed the other algorithms based on a rank normalized score. A prospective validation test set was chosen using prediction scores from the SVC models with ECFP fingerprints and were tested in vitro with 15 of 19 compounds (84% accuracy) predicted as active (≥20% inhibition) showed inhibition. Of these compounds, six (abamectin, asiaticoside, berbamine, doramectin, mobocertinib, and umbralisib) appear to be novel inhibitors of OATP1B1 not previously reported. These validated machine learning models can now be used to make predictions for drug-drug interactions for human OATP1B1 alongside other machine learning models for important drug transporters in our MegaTrans software.
AB - The uptake transporter OATP1B1 (SLC01B1) is largely localized to the sinusoidal membrane of hepatocytes and is a known victim of unwanted drug-drug interactions. Computational models are useful for identifying potential substrates and/or inhibitors of clinically relevant transporters. Our goal was to generate OATP1B1 in vitro inhibition data for [3H] estrone-3-sulfate (E3S) transport in CHO cells and use it to build machine learning models to facilitate a comparison of seven different classification models (Deep learning, Adaboosted decision trees, Bernoulli naïve bayes, k-nearest neighbors (knn), random forest, support vector classifier (SVC), logistic regression (lreg), and XGBoost (xgb)] using ECFP6 fingerprints to perform 5-fold, nested cross validation. In addition, we compared models using 3D pharmacophores, simple chemical descriptors alone or plus ECFP6, as well as ECFP4 and ECFP8 fingerprints. Several machine learning algorithms (SVC, lreg, xgb, and knn) had excellent nested cross validation statistics, particularly for accuracy, AUC, and specificity. An external test set containing 207 unique compounds not in the training set demonstrated that at every threshold SVC outperformed the other algorithms based on a rank normalized score. A prospective validation test set was chosen using prediction scores from the SVC models with ECFP fingerprints and were tested in vitro with 15 of 19 compounds (84% accuracy) predicted as active (≥20% inhibition) showed inhibition. Of these compounds, six (abamectin, asiaticoside, berbamine, doramectin, mobocertinib, and umbralisib) appear to be novel inhibitors of OATP1B1 not previously reported. These validated machine learning models can now be used to make predictions for drug-drug interactions for human OATP1B1 alongside other machine learning models for important drug transporters in our MegaTrans software.
KW - MegaTrans
KW - OATP1B1
KW - deep learning
KW - drug discovery
KW - machine learning
KW - support vector machine
KW - transporters
UR - http://www.scopus.com/inward/record.url?scp=85140851883&partnerID=8YFLogxK
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U2 - 10.1021/acs.molpharmaceut.2c00662
DO - 10.1021/acs.molpharmaceut.2c00662
M3 - Article
C2 - 36269563
AN - SCOPUS:85140851883
SN - 1543-8384
VL - 19
SP - 4320
EP - 4332
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 11
ER -