Blood–brain barrier penetration prediction enhanced by uncertainty estimation

Blood–brain barrier is a pivotal factor to be considered in the process of central nervous system (CNS) drug development, and it is of great significance to rapidly explore the blood–brain barrier permeability (BBBp) of compounds in silico in early drug discovery process. Here, we focus on whether and how uncertainty estimation methods improve in silico BBBp models. We briefly surveyed the current state of in silico BBBp prediction and uncertainty estimation methods of deep learning models, and curated an independent dataset to determine the reliability of the state-of-the-art algorithms. The results exhibit that, despite the comparable performance on BBBp prediction between graph neural networks-based deep learning models and conventional physicochemical-based machine learning models, the GROVER-BBBp model shows greatly improvement when using uncertainty estimations. In particular, the strategy combined Entropy and MC-dropout can increase the accuracy of distinguishing BBB + from BBB − to above 99% by extracting predictions with high confidence level (uncertainty score < 0.1). Case studies on preclinical/clinical drugs for Alzheimer’ s disease and marketed antitumor drugs that verified by literature proved the application value of uncertainty estimation enhanced BBBp prediction model, that may facilitate the drug discovery in the field of CNS diseases and metastatic brain tumors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13321-022-00619-2.