Some targets predicted by machine learning (ML) in drug discovery remain a challenge because of poor prediction. In this study, a new prediction model was developed and rat clearance (CL) was selected as a target because it is difficult to predict. A classification model was constructed using 1545 in-house compounds with rat CL data. The molecular descriptors calculated by Molecular Operating Environment (MOE), alvaDesc, and ADMET Predictor software were used to construct the prediction model. In conventional ML using 100 descriptors and random forest selected by DataRobot, the area under the curve (AUC) and accuracy (ACC) were 0.883 and 0.825, respectively. Conversely, the prediction model using DeepSnap and Deep Learning (DeepSnap-DL) with compound features as images had AUC and ACC of 0.905 and 0.832, respectively. We combined the two models (conventional ML and DeepSnap-DL) to develop a novel prediction model. Using the ensemble model with the mean of the predicted probabilities from each model improved the evaluation metrics (AUC = 0.943 and ACC = 0.874). In addition, a consensus model using the results of the agreement between classifications had an increased ACC (0.959). These combination models with a high level of predictive performance can be applied to rat CL as well as other pharmacokinetic parameters, pharmacological activity, and toxicity prediction. Therefore, these models will aid in the design of more rational compounds for the development of drugs.

Research into pharmacokinetics plays an important role in the development process of new drugs. Accurately predicting human pharmacokinetic parameters from preclinical data can increase the success rate of clinical trials. Since clearance (CL) which indicates the capacity of the entire body to process a drug is one of the most important parameters, many methods have been developed. However, there are still rooms to be improved for practical use in drug discovery research; "improving CL prediction accuracy" and "understanding the chemical structure of compounds in terms of pharmacokinetics". To improve those, this research proposes a multimodal learning method based on deep learning that takes not only the chemical structure of a drug but also rat CL as inputs. Good results were obtained compared with the conventional animal scale-up method; the geometric mean fold error was 2.68 and the proportion of compounds with prediction errors of 2-fold or less was 48.5%. Furthermore, it was found to be possible to infer the partial structure useful for CL prediction by a structure contributing factor inference method. The validity of these results of structural interpretation of metabolic stability was confirmed by chemists.

Despite their importance in determining the dosing regimen of drugs in the clinic, only a few studies have investigated methods for predicting blood-to-plasma concentration ratios (Rb). This study established an Rb prediction model incorporating typical human pharmacokinetics (PK) parameters. Experimental Rb values were compiled for 289 compounds, offering reliable predictions by expanding the applicability domain. Notably, it is the largest list of Rb values reported so far. Subsequently, human PK parameters calculated from plasma drug concentrations, including the volume of distribution (Vd), clearance, mean residence time, and plasma protein binding rate, as well as 2702 kinds of molecular descriptors, were used to construct quantitative structure–PK relationship models for Rb. Among the evaluated PK parameters, logVd correlated best with Rb (correlation coefficient of 0.47). Thus, in addition to molecular descriptors selected by XGBoost, logVd was employed to construct the prediction models. Among the analyzed algorithms, artificial neural networks gave the best results. Following optimization using six molecular descriptors and logVd, the model exhibited a correlation coefficient of 0.64 and a root-mean-square error of 0.205, which were superior to those previously reported for other Rb prediction methods. Since Vd values and chemical structures are known for most medications, the Rb prediction model described herein is expected to be valuable in clinical settings. Graphical abstract