Integrating Protein Dynamics into Structure-Based Drug Design via Full-Atom Stochastic Flows

The dynamic nature of proteins, influenced by ligand interactions, is essential for comprehending protein function and progressing drug discovery. Traditional structure-based drug design (SBDD) approaches typically target binding sites with rigid structures, limiting their practical application in drug development. While molecular dynamics simulation can theoretically capture all the biologically relevant conformations, the transition rate is dictated by the intrinsic energy barrier between them, making the sampling process computationally expensive. To overcome the aforementioned challenges, we propose to use generative modeling for SBDD considering conformational changes of protein pockets. We curate a dataset of apo and multiple holo states of protein-ligand complexes, simulated by molecular dynamics, and propose a full-atom flow model (and a stochastic version), named DynamicFlow, that learns to transform apo pockets and noisy ligands into holo pockets and corresponding 3D ligand molecules. Our method uncovers promising ligand molecules and corresponding holo conformations of pockets. Additionally, the resultant holo-like states provide superior inputs for traditional SBDD approaches, playing a significant role in practical drug discovery.

UniMatch: Universal Matching from Atom to Task for Few-Shot Drug Discovery

Drug discovery is crucial for identifying candidate drugs for various diseases.However, its low success rate often results in a scarcity of annotations, posing a few-shot learning problem. Existing methods primarily focus on single-scale features, overlooking the hierarchical molecular structures that determine different molecular properties. To address these issues, we introduce Universal Matching Networks (UniMatch), a dual matching framework that integrates explicit hierarchical molecular matching with implicit task-level matching via meta-learning, bridging multi-level molecular representations and task-level generalization. Specifically, our approach explicitly captures structural features across multiple levels, such as atoms, substructures, and molecules, via hierarchical pooling and matching, facilitating precise molecular representation and comparison. Additionally, we employ a meta-learning strategy for implicit task-level matching, allowing the model to capture shared patterns across tasks and quickly adapt to new ones. This unified matching framework ensures effective molecular alignment while leveraging shared meta-knowledge for fast adaptation. Our experimental results demonstrate that UniMatch outperforms state-of-the-art methods on the MoleculeNet and FS-Mol benchmarks, achieving improvements of 2.87% in AUROC and 6.52% in delta AUPRC. UniMatch also shows excellent generalization ability on the Meta-MolNet benchmark.

Group Ligands Docking to Protein Pockets

Molecular docking is a key task in computational biology that has attracted increasing interest from the machine learning community. While existing methods have achieved success, they generally treat each protein-ligand pair in isolation. Inspired by the biochemical observation that ligands binding to the same target protein tend to adopt similar poses, we propose \textsc{GroupBind}, a novel molecular docking framework that simultaneously considers multiple ligands docking to a protein. This is achieved by introducing an interaction layer for the group of ligands and a triangle attention module for embedding protein-ligand and group-ligand pairs. By integrating our approach with diffusion-based docking model, we set a new S performance on the PDBBind blind docking benchmark, demonstrating the effectiveness of our proposed molecular docking paradigm.

Contextual Representation Anchor Network to Alleviate Selection Bias in Few-Shot Drug Discovery

In the drug discovery process, the low success rate of drug candidate screening often leads to insufficient labeled data, causing the few-shot learning problem in molecular property prediction. Existing methods for few-shot molecular property prediction overlook the sample selection bias, which arises from non-random sample selection in chemical experiments. This bias in data representativeness leads to suboptimal performance. To overcome this challenge, we present a novel method named contextual representation anchor Network (CRA), where an anchor refers to a cluster center of the representations of molecules and serves as a bridge to transfer enriched contextual knowledge into molecular representations and enhance their expressiveness. CRA introduces a dual-augmentation mechanism that includes context augmentation, which dynamically retrieves analogous unlabeled molecules and captures their task-specific contextual knowledge to enhance the anchors, and anchor augmentation, which leverages the anchors to augment the molecular representations. We evaluate our approach on the MoleculeNet and FS-Mol benchmarks, as well as in domain transfer experiments. The results demonstrate that CRA outperforms the state-of-the-art by 2.60% and 3.28% in AUC and $\Delta$AUC-PR metrics, respectively, and exhibits superior generalization capabilities.

Reprogramming Pretrained Target-Specific Diffusion Models for Dual-Target Drug Design

Dual-target therapeutic strategies have become a compelling approach and attracted significant attention due to various benefits, such as their potential in overcoming drug resistance in cancer therapy. Considering the tremendous success that deep generative models have achieved in structure-based drug design in recent years, we formulate dual-target drug design as a generative task and curate a novel dataset of potential target pairs based on synergistic drug combinations. We propose to design dual-target drugs with diffusion models that are trained on single-target protein-ligand complex pairs. Specifically, we align two pockets in 3D space with protein-ligand binding priors and build two complex graphs with shared ligand nodes for SE(3)-equivariant composed message passing, based on which we derive a composed drift in both 3D and categorical probability space in the generative process. Our algorithm can well transfer the knowledge gained in single-target pretraining to dual-target scenarios in a zero-shot manner. We also repurpose linker design methods as strong baselines for this task. Extensive experiments demonstrate the effectiveness of our method compared with various baselines.

ProteinBench: A Holistic Evaluation of Protein Foundation Models

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

Decomposed Direct Preference Optimization for Structure-Based Drug Design

Diffusion models have achieved promising results for Structure-Based Drug Design (SBDD). Nevertheless, high-quality protein subpocket and ligand data are relatively scarce, which hinders the models' generation capabilities. Recently, Direct Preference Optimization (DPO) has emerged as a pivotal tool for the alignment of generative models such as large language models and diffusion models, providing greater flexibility and accuracy by directly aligning model outputs with human preferences. Building on this advancement, we introduce DPO to SBDD in this paper. We tailor diffusion models to pharmaceutical needs by aligning them with elaborately designed chemical score functions. We propose a new structure-based molecular optimization method called DecompDPO, which decomposes the molecule into arms and scaffolds and performs preference optimization at both local substructure and global molecule levels, allowing for more precise control with fine-grained preferences. Notably, DecompDPO can be effectively used for two main purposes: (1) fine-tuning pretrained diffusion models for molecule generation across various protein families, and (2) molecular optimization given a specific protein subpocket after generation. Extensive experiments on the CrossDocked2020 benchmark show that DecompDPO significantly improves model performance in both molecule generation and optimization, with up to 100% Median High Affinity and a 54.9% Success Rate.

Implicit Multi-Spectral Transformer: An Lightweight and Effective Visible to Infrared Image Translation Model

In the field of computer vision, visible light images often exhibit low contrast in low-light conditions, presenting a significant challenge. While infrared imagery provides a potential solution, its utilization entails high costs and practical limitations. Recent advancements in deep learning, particularly the deployment of Generative Adversarial Networks (GANs), have facilitated the transformation of visible light images to infrared images. However, these methods often experience unstable training phases and may produce suboptimal outputs. To address these issues, we propose a novel end-to-end Transformer-based model that efficiently converts visible light images into high-fidelity infrared images. Initially, the Texture Mapping Module and Color Perception Adapter collaborate to extract texture and color features from the visible light image. The Dynamic Fusion Aggregation Module subsequently integrates these features. Finally, the transformation into an infrared image is refined through the synergistic action of the Color Perception Adapter and the Enhanced Perception Attention mechanism. Comprehensive benchmarking experiments confirm that our model outperforms existing methods, producing infrared images of markedly superior quality, both qualitatively and quantitatively. Furthermore, the proposed model enables more effective downstream applications for infrared images than other methods.

Antigen-Specific Antibody Design via Direct Energy-based Preference Optimization

Antibody design, a crucial task with significant implications across various disciplines such as therapeutics and biology, presents considerable challenges due to its intricate nature. In this paper, we tackle antigen-specific antibody design as a protein sequence-structure co-design problem, considering both rationality and functionality. Leveraging a pre-trained conditional diffusion model that jointly models sequences and structures of complementarity-determining regions (CDR) in antibodies with equivariant neural networks, we propose direct energy-based preference optimization to guide the generation of antibodies with both rational structures and considerable binding affinities to given antigens. Our method involves fine-tuning the pre-trained diffusion model using a residue-level decomposed energy preference. Additionally, we employ gradient surgery to address conflicts between various types of energy, such as attraction and repulsion. Experiments on RAbD benchmark show that our approach effectively optimizes the energy of generated antibodies and achieves state-of-the-art performance in designing high-quality antibodies with low total energy and high binding affinity, demonstrating the superiority of our approach.

Stabilizing Policy Gradients for Stochastic Differential Equations via Consistency with Perturbation Process

Considering generating samples with high rewards, we focus on optimizing deep neural networks parameterized stochastic differential equations (SDEs), the advanced generative models with high expressiveness, with policy gradient, the leading algorithm in reinforcement learning. Nevertheless, when applying policy gradients to SDEs, since the policy gradient is estimated on a finite set of trajectories, it can be ill-defined, and the policy behavior in data-scarce regions may be uncontrolled. This challenge compromises the stability of policy gradients and negatively impacts sample complexity. To address these issues, we propose constraining the SDE to be consistent with its associated perturbation process. Since the perturbation process covers the entire space and is easy to sample, we can mitigate the aforementioned problems. Our framework offers a general approach allowing for a versatile selection of policy gradient methods to effectively and efficiently train SDEs. We evaluate our algorithm on the task of structure-based drug design and optimize the binding affinity of generated ligand molecules. Our method achieves the best Vina score -9.07 on the CrossDocked2020 dataset.