Development of Novel Methods for QSAR Modeling by Machine Learning Repeatedly: A Case Study on Drug Distribution to Each Tissue

Artificial intelligence is expected to help identify excellent candidates in drug discovery. However, we face a lack of data, as it is time-consuming and expensive to acquire raw data perfectly for many compounds. Hence, we tried to develop a novel quantitative structure-activity relationship (QSAR) method to predict a parameter more precisely from an incomplete data set via optimizing data handling by making use of predicted explanatory variables. As a case study we focused on the tissue-to-plasma partition coefficient (Kp), which is an important parameter for understanding drug distribution in tissues and building the physiologically based pharmacokinetic model and is a representative of small and sparse data sets. In this study, we predicted the Kp values of 119 compounds in nine tissues (adipose, brain, gut, heart, kidney, liver, lung, muscle, and skin), although some of these were not available. To fill the missing values in Kp for each tissue, first we predicted those Kp values by the nonmissing data set using a random forest (RF) model with