Transformer-based deep learning method for optimizing ADMET properties of lead compounds

A successful drug needs to exhibit both effective pharmacodynamics (PD) and safe pharmacokinetics (PK). However, the coordinated optimization of PD and PK properties in molecule generation tasks remains a great challenge for most existing methods, especially when they focus on the pursuit of affinity and selectivity for the lead compound. Thus, molecular optimization for PK properties is a critical step in the drug discovery pipeline, in which absorption, distribution, metabolism, excretion and toxicity (ADMET) property predictive models play an increasingly important role by providing an effective method to assess multiple PK properties of compounds. Here, we proposed a Graph Bert-based ADMET prediction model that achieves state-of-the-art performance on the public dataset Therapeutics Data Commons (TDC) by combining molecular graph features and descriptor features, with 11 tasks ranked first and 20 tasks ranked in the top 3. Based on this prediction model, we trained a Transformer model with multiple properties as constraints for learning the structural transformations involved in MMP and the accompanying property changes. The experimental results show that the trained Constraints-Transformer can implement targeted modifications to the starting molecule, while preserving the core scaffold. Moreover, molecular docking and binding mode analysis demonstrate that the optimized molecules still retain the activity and selectivity for biological targets. Therefore, the proposed method accounts for biological activity and ADMET properties simultaneously. Finally, a webserver containing ADMET property prediction and molecular optimization functions is provided, enabling chemists to improve the properties of starting molecules individually.