A curated diverse molecular database of blood-brain barrier permeability with chemical descriptors

Abstract

The highly-selective blood-brain barrier (BBB) prevents neurotoxic substances in blood from crossing into the extracellular fluid of the central nervous system (CNS). As such, the BBB has a close relationship with CNS disease development and treatment, so predicting whether a substance crosses the BBB is a key task in lead discovery for CNS drugs. Machine learning (ML) is a promising strategy for predicting the BBB permeability, but existing studies have been limited by small datasets with limited chemical diversity. To mitigate this issue, we present a large benchmark dataset, B3DB, complied from 50 published resources and categorized based on experimental uncertainty. A subset of the molecules in B3DB has numerical log BB values (1058 compounds), while the whole dataset has categorical (BBB+ or BBB−) BBB permeability labels (7807). The dataset is freely available at https://github.com/theochem/B3DB and 10.6084/m9.figshare.15634230.v3 (version 3). We also provide some physicochemical properties of the molecules. By analyzing these properties, we can demonstrate some physiochemical similarities and differences between BBB+ and BBB− compounds.

A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors

“…To prove that the 1,167 compounds of the ABC_BPMDS have a balanced distribution of physicochemical attributes, the ABC_BPMDS was analyzed for the CLogP, MW, MR, and TPSA using MOE version 2019.01. Figure 3 demonstrates that these physicochemical properties are normally distributed within the ABC_BPMDS comparable to other reported datasets 23 , 70 . Table 4 summarizes the median and mean values of CLogP, MW, MR, and TPSA of the entire ABC_BPMDS as well as important sub-classes.…”

“…Unfortunately, comprehensive binary datasets do not exist for ABC transporters. However, the knowledge about such binary fingerprints could facilitate the development of (i) drugs that avoid clearance mediated by ABC transporters [ e.g ., targeting the BBB to treat central nervous system-(CNS)-related diseases 23 ]; (ii) agents targeting ABC transporters to study their expression and/or function with state-of-the-art imaging techniques [ e.g ., by positron emission tomography (PET) 16 ]; (iii) drugs that selectively target well-studied ABC transporters in human diseases ( e.g ., cancer 1 , 3 , 4 , 6 , 8 ); (iv) broad-spectrum drugs that target several ABC transporters to ameliorate/cure an ABC transporter-associated pathological condition 24 ; (v) polypharmacological agents to target and study particularly less- and under-studied ABC transporters by a multitargeting approach 7 , 25 – 27 ; or (vi) combined/extended fingerprints to create high-quality compound collections that would provide a starting point of polypharmacology-focused virtual screenings 7 .…”

Brain and Retinal Organoids for Disease Modeling: The Importance of In Vitro Blood–Brain and Retinal Barriers Studies

“…In addition, the compounds with the ability to cross the BBB should have a log[brain]/[blood] (logBB) ≥ 0.00 [ 138 ]. Recently, a dataset for modeling BBB permeability of small molecules providing some physiochemical similarities and differences was published [ 139 ]. Several biomarkers that can help to assess the BBB permeability and integrity in vitro or in vivo are reported [ 140 ].…”

Computational Analysis of Pathogenetic Pathways in Alzheimer’s Disease and Prediction of Potential Therapeutic Drugs

“…Analysis was performed using the Morpheus web-based application (https://software.broadinstitute.org/morpheus/, accessed on 15 April 2022). Among the predicted drugs, we identified those with blood-brain barrier (BBB) permeability by interrogating the large benchmark data set, B3DB, which includes 7807 small molecules [12].…”