Predicting blood-brain barrier permeability of molecules with a large language model and machine learning.

Predicting the blood-brain barrier (BBB) permeability of small-molecule compounds using a novel artificial intelligence platform is necessary for drug discovery. Machine learning and a large language model on artificial intelligence (AI) tools improve the accuracy and shorten the time for new drug development. The primary goal of this research is to develop artificial intelligence (AI) computing models and novel deep learning architectures capable of predicting whether molecules can permeate the human blood-brain barrier (BBB). The in silico (computational) and in vitro (experimental) results were validated by the Natural Products Research Laboratories (NPRL) at China Medical University Hospital (CMUH). The transformer-based MegaMolBART was used as the simplified molecular input line entry system (SMILES) encoder with an XGBoost classifier as an in silico method to check if a molecule could cross through the BBB. We used Morgan or Circular fingerprints to apply the Morgan algorithm to a set of atomic invariants as a baseline encoder also with an XGBoost classifier to compare the results. BBB permeability was assessed in vitro using three-dimensional (3D) human BBB spheroids (human brain microvascular endothelial cells, brain vascular pericytes, and astrocytes). Using multiple BBB databases, the results of the final in silico transformer and XGBoost model achieved an area under the receiver operating characteristic curve of 0.88 on the held-out test dataset. Temozolomide (TMZ) and 21 randomly selected BBB permeable compounds (Pred scores = 1, indicating BBB-permeable) from the NPRL penetrated human BBB spheroid cells. No evidence suggests that ferulic acid or five BBB-impermeable compounds (Pred scores < 1.29423E-05, which designate compounds that pass through the human BBB) can pass through the spheroid cells of the BBB. Our validation of in vitro experiments indicated that the in silico prediction of small-molecule permeation in the BBB model is accurate. Transformer-based models like MegaMolBART, leveraging the SMILES representations of molecules, show great promise for applications in new drug discovery. These models have the potential to accelerate the development of novel targeted treatments for disorders of the central nervous system.

Automatic detection and characterization of quantitative phase images of thalassemic red blood cells using a mask region-based convolutional neural network.

SIGNIFICANCE: Label-free quantitative phase imaging is a promising technique for the automatic detection of abnormal red blood cells (RBCs) in real time. Although deep-learning techniques can accurately detect abnormal RBCs from quantitative phase images efficiently, their applications in diagnostic testing are limited by the lack of transparency. More interpretable results such as morphological and biochemical characteristics of individual RBCs are highly desirable. AIM: An end-to-end deep-learning model was developed to efficiently discriminate thalassemic RBCs (tRBCs) from healthy RBCs (hRBCs) in quantitative phase images and segment RBCs for single-cell characterization. APPROACH: Two-dimensional quantitative phase images of hRBCs and tRBCs were acquired using digital holographic microscopy. A mask region-based convolutional neural network (Mask R-CNN) model was trained to discriminate tRBCs and segment individual RBCs. Characterization of tRBCs was achieved utilizing SHapley Additive exPlanation analysis and canonical correlation analysis on automatically segmented RBC phase images. RESULTS: The implemented model achieved 97.8% accuracy in detecting tRBCs. Phase-shift statistics showed the highest influence on the correct classification of tRBCs. Associations between the phase-shift features and three-dimensional morphological features were revealed. CONCLUSIONS: The implemented Mask R-CNN model accurately identified tRBCs and segmented RBCs to provide single-RBC characterization, which has the potential to aid clinical decision-making.