Deep-PK: deep learning for small molecule pharmacokinetic and toxicity prediction.

Evaluating pharmacokinetic properties of small molecules is considered a key feature in most drug development and high-throughput screening processes. Generally, pharmacokinetics, which represent the fate of drugs in the human body, are described from four perspectives: absorption, distribution, metabolism and excretion-all of which are closely related to a fifth perspective, toxicity (ADMET). Since obtaining ADMET data from in vitro, in vivo or pre-clinical stages is time consuming and expensive, many efforts have been made to predict ADMET properties via computational approaches. However, the majority of available methods are limited in their ability to provide pharmacokinetics and toxicity for diverse targets, ensure good overall accuracy, and offer ease of use, interpretability and extensibility for further optimizations. Here, we introduce Deep-PK, a deep learning-based pharmacokinetic and toxicity prediction, analysis and optimization platform. We applied graph neural networks and graph-based signatures as a graph-level feature to yield the best predictive performance across 73 endpoints, including 64 ADMET and 9 general properties. With these powerful models, Deep-PK supports molecular optimization and interpretation, aiding users in optimizing and understanding pharmacokinetics and toxicity for given input molecules. The Deep-PK is freely available at https://biosig.lab.uq.edu.au/deeppk/.

Machine learning framework to predict pharmacokinetic profile of small molecule drugs based on chemical structure.

Accurate prediction of a new compound's pharmacokinetic (PK) profile is pivotal for the success of drug discovery programs. An initial assessment of PK in preclinical species and humans is typically performed through allometric scaling and mathematical modeling. These methods use parameters estimated from in vitro or in vivo experiments, which although helpful for an initial estimation, require extensive animal experiments. Furthermore, mathematical models are limited by the mechanistic underpinning of the drugs' absorption, distribution, metabolism, and elimination (ADME) which are largely unknown in the early stages of drug discovery. In this work, we propose a novel methodology in which concentration versus time profile of small molecules in rats is directly predicted by machine learning (ML) using structure-driven molecular properties as input and thus mitigating the need for animal experimentation. The proposed framework initially predicts ADME properties based on molecular structure and then uses them as input to a ML model to predict the PK profile. For the compounds tested, our results demonstrate that PK profiles can be adequately predicted using the proposed algorithm, especially for compounds with Tanimoto score greater than 0.5, the average mean absolute percentage error between predicted PK profile and observed PK profile data was found to be less than 150%. The suggested framework aims to facilitate PK predictions and thus support molecular screening and design earlier in the drug discovery process.

Prediction method of pharmacokinetic parameters of small molecule drugs based on GCN network model.

CONTEXT: Accurately predicting plasma protein binding rate (PPBR) and oral bioavailability (OBA) helps to better reveal the absorption and distribution of drugs in the human body and subsequent drug design. Although machine learning models have achieved good results in prediction accuracy, they often suffer from insufficient accuracy when dealing with data with irregular topological structures. METHODS: In view of this, this study proposes a pharmacokinetic parameter prediction framework based on graph convolutional networks (GCN), which predicts the PPBR and OBA of small molecule drugs. In the framework, GCN is first used to extract spatial feature information on the topological structure of drug molecules, in order to better learn node features and association information between nodes. Then, based on the principle of drug similarity, this study calculates the similarity between small molecule drugs, selects different thresholds to construct datasets, and establishes a prediction model centered on the GCN algorithm. The experimental results show that compared with traditional machine learning prediction models, the prediction model constructed based on the GCN method performs best on PPBR and OBA datasets with an inter-molecular similarity threshold of 0.25, with MAE of 0.155 and 0.167, respectively. In addition, in order to further improve the accuracy of the prediction model, GCN is combined with other algorithms. Compared to using a single GCN method, the distribution of the predicted values obtained by the combined model is highly consistent with the true values. In summary, this work provides a new method for improving the rate of early drug screening in the future.