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Computational drug repurposing is an efficient method to utilize existing knowledge for understanding and predicting their effect on neurological diseases. The ability of a molecule to cross the blood-brain barrier is a primary criteria for effective therapy. Thus, accurate predictions by employing Machine learning models can effectively identify the drug candidates that could be repurposed for neurological conditions. This study comprehensively analyzes the performance of the well-known machine learning models on two different datasets to overcome dataset-related biases. We found that random forest and extratrees (i.e., tree-based ensembled models) have the highest accuracy with mol2vec fingerprint for BBB permeability prediction, attaining AUC_ROC of 0.9453 and 0.9601 on BBB and B3DB dataset, respectively. Additionally, we have analyzed the impact of the data balancing technique (i.e., SMOTE) to improve the specificity of the models. Finally, we have explored the impact of different fingerprint combinations on accuracy. By employing SMOTE and fingerprint combination, SVC attains the highest AUC_ROC of 0.9511 on BBB dataset. Finally, we used the best-performing models of the B3DB dataset to evaluate the BBB permeability for drugs intended to be used for repurposing. Model validation for repurposing predicted the non-passage for most antihypertensive drugs and passage for CYP17A1 cancer drugs.

Owing to limited drug testing possibilities in pregnant population, the development of computational algorithms is crucial to predict the fate of drugs in the placental barrier; it could serve as an alternative to animal testing. The ability of a molecule to effectively cross the placental barrier and reach the fetus determines the drug’s toxicological effects on the fetus. In this regard, our study aims to predict the permeability of molecules across the placental barrier. Based on publicly available datasets, several machine learning models are comprehensively analysed across different fingerprints and toolkits to find the best suitable models. Several dataset analysis models are utilised to study the data diversity. Further, this study demonstrates the application of neural network-based models to effectively predict the permeability. K-nearest neighbour (KNN), standard vector classifier (SVC) and Multi-layer perceptron (MLP) are found to be the best-performing models with a prediction percentage of 82%, 86.4% and 90.8%, respectively. Different models are compared to predict the chosen set of drugs, drugs like Aliskiren, some insulin secretagogues and glucocorticoids are found to be negative while predicting the permeability.

More information about a person's genetic makeup, drug response, multi-omics response, and genomic response is now available leading to a gradual shift towards personalized treatment. Additionally, the promotion of non-animal testing has fueled the computational toxicogenomics as a pivotal part of the next-gen risk assessment paradigm. Artificial Intelligence (AI) has the potential to provid new ways analyzing the patient data and making predictions about treatment outcomes or toxicity. As personalized medicine and toxicogenomics involve huge data processing, AI can expedite this process by providing powerful data processing, analysis, and interpretation algorithms. AI can process and integrate a multitude of data including genome data, patient records, clinical data and identify patterns to derive predictive models anticipating clinical outcomes and assessing the risk of any personalized medicine approaches. In this article, we have studied the current trends and future perspectives in personalized medicine & toxicology, the role of toxicogenomics in connecting the two fields, and the impact of AI on personalized medicine & toxicology. In this work, we also study the key challenges and limitations in personalized medicine, toxicogenomics, and AI in order to fully realize their potential.

Increasing data on the infection indicate that maternal infections are severe. Under the realms of vaccine development, virus‐like particles (VLP)/nanoparticles (NPs) hold the promise of targeted control of therapeutics transfer across the placental barrier with the potential to trigger innate immune responses. Though the placenta is known to act as a barrier against exogenous materials, viruses exploit the transport systems and overcome the barrier properties. VLPs can be strategically designed to obtain the necessary mechanisms for navigation across the placenta and immune response. However, several knowledge gaps on the chemical, viral transmission strategies and the host defense response exist owing to the highly dynamic etiology of the placental barrier. This further complicates the toxicological analysis of the developed therapeutics. Herein, placental physiology and functions are discussed in significance with chemical toxicology, viral infections, and the host defense. Further, the promising applications of VLPs and perspective on their design to overcome the placental gatekeeper to gain the necessary immune response or therapy are provided. Finally, a holistic approach to various bioengineering models for studying chemical toxicants, viral infections, and effects of VLPs is provided to facilitate better translation of these VLPs to clinical applications.

A hybrid blood–brain barrier (BBB)-on-chip cell culture device is proposed in this study by integrating microcontact printing and perfusion co-culture to facilitate the study of BBB function under high biological fidelity. This is achieved by crosslinking brain extracellular matrix (ECM) proteins to the transwell membrane at the luminal surface and adapting inlet–outlet perfusion on the porous transwell wall. While investigating the anatomical hallmarks of the BBB, tight junction proteins revealed tortuous zonula occludens (ZO-1), and claudin expressions with increased interdigitation in the presence of astrocytes were recorded. Enhanced adherent junctions were also observed. This junctional phenotype reflects in-vivo-like features related to the jamming of cell borders to prevent paracellular transport. Biochemical regulation of BBB function by astrocytes was noted by the transient intracellular calcium effluxes induced into endothelial cells. Geometry-force control of astrocyte–endothelial cell interactions was studied utilizing traction force microscopy (TFM) with fluorescent beads incorporated into a micropatterned polyacrylamide gel (PAG). We observed the directionality and enhanced magnitude in the traction forces in the presence of astrocytes. In the future, we envisage studying transendothelial electrical resistance (TEER) and the effect of chemomechanical stimulations on drug/ligand permeability and transport. The BBB-on-chip model presented in this proposal should serve as an in vitro surrogate to recapitulate the complexities of the native BBB cellular milieus.