ShallowBench: Benchmarking Generative Drug Design Models on Shallow-Pocket Targets

While generative AI models have demonstrated remarkable success in structure-based drug design, they predominantly rely on deep binding pockets and struggle to sample effective ligands for challenging low-pocketability targets, such as the historically "undruggable" oncology targets KRAS and MYC. To address this gap, we introduce ShallowBench, a strictly curated benchmark of 5,780 shallow-pocket targets extracted from CrossDocked2020. By computing the difference between an Alpha Shape "lid" volume and the underlying protein atom voxel volume, we successfully isolated targets with low concavity while ensuring sufficient surface area for binding. Evaluating various state-of-the-art generative models reveals weaker predicted binding affinity on these low-concavity interfaces. ShallowBench therefore provides a rigorous benchmark for generative biology models and highlights the necessity of new architectural innovations or loss functions capable of navigating these challenging targets.

BiasGRPO: Stabilizing Bias Mitigation in High-Variance Reward Landscapes via Group-Relative Policy Optimization

Mitigating social bias in Large Language Models (LLMs) presents a distinct alignment challenge: unlike verifiable tasks, bias lacks a single ground truth, creating a high-variance, subjective reward landscape. Previous preference-based fine-tuning methods have major trade-offs: Direct Preference Optimization (DPO) is limited by the lack of exploration inherent in offline training, while Proximal Policy Optimization (PPO) can lead to training instability due to potentially unreliable critic estimates. In this paper, we propose BiasGRPO, a framework using Group Relative Policy Optimization (GRPO) to stabilize alignment by normalizing rewards across a group of sampled completions. By substituting the value function with a group-relative baseline, our approach reduces instability while maintaining the exploration benefits of online training. We find that BiasGRPO outperforms DPO and PPO across multiple benchmarks, indicating its effectiveness. To adapt GRPO, we synthetically extend a dataset spanning multiple domains and contexts. We also create and release a custom bias reward model that effectively guides generation while being highly compute-efficient and avoiding knowledge degradation, providing a valuable resource that can be seamlessly integrated into multi-objective RLHF pipelines.