Development of an a priori computational approach for brain uptake of compounds in an insect model system

• Published in: Bioorganic & medicinal chemistry letters 2021-05, Vol.40, p.127930-127930, Article 127930
• Main Authors: Geldenhuys, Werner J., Bloomquist, Jeffrey R.
• Format: Article
• Language: English
• Subjects: Animals; Blood–brain barrier; Brain - metabolism; Central Nervous System Agents - chemistry; Central Nervous System Agents - metabolism; Cheminformatics; Data mining; Databases, Chemical - statistics & numerical data; Grasshoppers - metabolism; Linear Models; Models, Biological; Neural Networks, Computer; QSAR; QSPR; Support Vector Machine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.127930

[Display omitted] Delivery of compounds to the brain is critical for the development of effective treatment therapies of multiple central nervous system diseases. Recently a novel insect-based brain uptake model was published utilizing a locust brain ex vivo system. The goal of our study was to develop a priori, in silico cheminformatic models to describe brain uptake in this insect model, as well as evaluate the predictive ability. The machine learning program Orange® was used to evaluate several machine learning (ML) models on a published data set of 25 known drugs, with in vitro data generated by a single laboratory group to reduce inherent inter-laboratory variability. The ML models included in this study were linear regression (LR), support vector machines (SVN), k-nearest neighbor (kNN) and neural nets (NN). The quantitative structure–property relationship models were able to correlate experimental logCtot (concentration of compound in brain) and predicted brain uptake of r2 > 0.5, with the descriptors log(P*MW−0.5) and hydrogen bond donor used in LR, SVN and KNN, while log(P*MW−0.5) and total polar surface area (TPSA) descriptors used in the NN models. Our results indicate that the locust insect model is amenable to data mining chemoinformatics and in silico model development in CNS drug discovery pipelines.