Tianming Xu

Xuefeng Liu, Songhao Jiang, Qinan Huang et al.

Fragment-Based Drug Discovery (FBDD) is a popular approach in early drug development, but designing effective linkers to combine disconnected molecular fragments into chemically and pharmacologically viable candidates remains challenging. Further complexity arises when fragments contain structural redundancies, like duplicate rings, which cannot be addressed by simply adding or removing atoms or bonds. To address these challenges in a unified framework, we introduce FragmentGPT, which integrates two core components: (1) a novel chemically-aware, energy-based bond cleavage pre-training strategy that equips the GPT-based model with fragment growing, linking, and merging capabilities, and (2) a novel Reward Ranked Alignment with Expert Exploration (RAE) algorithm that combines expert imitation learning for diversity enhancement, data selection and augmentation for Pareto and composite score optimality, and Supervised Fine-Tuning (SFT) to align the learner policy with multi-objective goals. Conditioned on fragment pairs, FragmentGPT generates linkers that connect diverse molecular subunits while simultaneously optimizing for multiple pharmaceutical goals. It also learns to resolve structural redundancies-such as duplicated fragments-through intelligent merging, enabling the synthesis of optimized molecules. FragmentGPT facilitates controlled, goal-driven molecular assembly. Experiments and ablation studies on real-world cancer datasets demonstrate its ability to generate chemically valid, high-quality molecules tailored for downstream drug discovery tasks.

Wentao Chen, Jiwei Li, Xichen Xu et al.

[$^{18}$F]fluorodeoxyglucose (FDG) positron emission tomography (PET) has emerged as a crucial tool in identifying the epileptic focus, especially in cases where magnetic resonance imaging (MRI) diagnosis yields indeterminate results. FDG PET can provide the metabolic information of glucose and help identify abnormal areas that are not easily found through MRI. However, the effectiveness of FDG PET-based assessment and diagnosis depends on the selection of a healthy control group. The healthy control group typically consists of healthy individuals similar to epilepsy patients in terms of age, gender, and other aspects for providing normal FDG PET data, which will be used as a reference for enhancing the accuracy and reliability of the epilepsy diagnosis. However, significant challenges arise when a healthy PET control group is unattainable. Yaakub \emph{et al.} have previously introduced a Pix2PixGAN-based method for MRI to PET translation. This method used paired MRI and FDG PET scans from healthy individuals for training, and produced pseudo normal FDG PET images from patient MRIs that are subsequently used for lesion detection. However, this approach requires a large amount of high-quality, paired MRI and PET images from healthy control subjects, which may not always be available. In this study, we investigated unsupervised learning methods for unpaired MRI to PET translation for generating pseudo normal FDG PET for epileptic focus localization. Two deep learning methods, CycleGAN and SynDiff, were employed, and we found that diffusion-based method achieved improved performance in accurately localizing the epileptic focus.