A Novel Graph Neural Network Methodology to Investigate Dihydroorotate Dehydrogenase Inhibitors in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a particularly aggressive tumor subtype, and dihydroorotate dehydrogenase (DHODH) has been demonstrated to be a therapeutic target for SCLC. Network pharmacology analysis and virtual screening were utilized to find out related proteins and investigate candidates with high docking capacity to multiple targets. Graph neural networks (GNNs) and machine learning were used to build reliable predicted models. We proposed a novel concept of multi-GNNs, and then built three multi-GNN models called GIAN, GIAT, and SGCA, which achieved satisfactory results in our dataset containing 532 molecules with all R² values greater than 0. 92 on the training set and higher than 0. 8 on the test set. Compared with machine learning algorithms, random forest (RF), and support vector regression (SVR), multi-GNNs had a better modeling effect and higher precision. Furthermore, the long-time 300 ns molecular dynamics simulation verified the stability of the protein–ligand complexes. The result showed that ZINC8577218, ZINC95618747, and ZINC4261765 might be the potentially potent inhibitors for DHODH. Multi-GNNs show great performance in practice, making them a promising field for future research. We therefore suggest that this novel concept of multi-GNNs is a promising protocol for drug discovery.