Target Specific De Novo Design of Drug Candidate Molecules with Graph Transformer-based Generative Adversarial Networks

Discovering novel drug candidate molecules is one of the most fundamental and critical steps in drug development. Generative deep learning models, which create synthetic data given a probability distribution, have been developed with the purpose of picking completely new samples from a partially known space. Generative models offer high potential for designing de novo molecules; however, in order for them to be useful in real-life drug development pipelines, these models should be able to design target-specific molecules, which is the next step in this field. In this study, we propose DrugGEN, for the de novo design of drug candidate molecules that interact with selected target proteins. The proposed system represents compounds and protein structures as graphs and processes them via serially connected two generative adversarial networks comprising graph transformers. DrugGEN is trained using a large dataset of compounds from ChEMBL and target-specific bioactive molecules, to design effective and specific inhibitory molecules against the AKT1 protein, which has critical importance for developing treatments against various types of cancer. On fundamental benchmarks, DrugGEN models have either competitive or better performance against other methods. To assess the target-specific generation performance, we conducted further in silico analysis with molecular docking and deep learning-based bioactivity prediction. Results indicate that de novo molecules have high potential for interacting with the AKT1 protein structure in the level of its native ligand. DrugGEN can be used to design completely novel and effective target-specific drug candidate molecules for any druggable protein, given target features and a dataset of experimental bioactivities. Code base, datasets, results and trained models of DrugGEN are available at https://github.com/HUBioDataLab/DrugGEN

Graph Mixer Networks

In recent years, the attention mechanism has demonstrated superior performance in various tasks, leading to the emergence of GAT and Graph Transformer models that utilize this mechanism to extract relational information from graph-structured data. However, the high computational cost associated with the Transformer block, as seen in Vision Transformers, has motivated the development of alternative architectures such as MLP-Mixers, which have been shown to improve performance in image tasks while reducing the computational cost. Despite the effectiveness of Transformers in graph-based tasks, their computational efficiency remains a concern. The logic behind MLP-Mixers, which addresses this issue in image tasks, has the potential to be applied to graph-structured data as well. In this paper, we propose the Graph Mixer Network (GMN), also referred to as Graph Nasreddin Nets (GNasNets), a framework that incorporates the principles of MLP-Mixers for graph-structured data. Using a PNA model with multiple aggregators as the foundation, our proposed GMN has demonstrated improved performance compared to Graph Transformers. The source code is available publicly at https://github.com/asarigun/GraphMixerNetworks.