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Yuwei Yang

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6 papers

2 author rows

TMLR Journal 2025 Journal Article

Decomposed Direct Preference Optimization for Structure-Based Drug Design

Xiwei Cheng
Xiangxin Zhou
Yuwei Yang
Yu Bao
Quanquan Gu

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 aligning generative models with human preferences. In this paper, we propose DecompDpo, a structure-based optimization method aligns diffusion models with pharmaceutical needs using multi-granularity preference pairs. DecompDpo introduces decomposition into the optimization objectives and obtains preference pairs at the molecule or decomposed substructure level based on each objective’s decomposability. Additionally, DecompDpo introduces a physics-informed energy term to ensure reasonable molecular conformations in the optimization results. 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, achieving up to 98.5% Med. High Affinity and a 43.9% success rate for molecule generation, and 100% Med. High Affinity and a 52.1% success rate for targeted molecule optimization.

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NeurIPS Conference 2025 Conference Paper

MMMG: A Massive, Multidisciplinary, Multi-Tier Generation Benchmark for Text-to-Image Reasoning

Yuxuan Luo
Ryan Yuan
Junwen Chen
Haonan Cai
Ziyi Yue
Yuwei Yang
Fatima Zohra Daha
Ji Li

In this paper, we introduce knowledge image generation as a new task, alongside the Massive Multi-Discipline Multi-Tier Knowledge-Image Generation Benchmark (MMMG) to probe the reasoning capability of image generation models. Knowledge images have been central to human civilization and to the mechanisms of human learning—a fact underscored by dual-coding theory and the picture-superiority effect. Generating such images is challenging, demanding multimodal reasoning that fuses world knowledge with pixel-level grounding into clear explanatory visuals. To enable comprehensive evaluation, MMMG offers $4, 456$ expert-validated (knowledge) image-prompt pairs spanning $10$ disciplines, $6$ educational levels, and diverse knowledge formats such as charts, diagrams, and mind maps. To eliminate confounding complexity during evaluation, we adopt a unified Knowledge Graph (KG) representation. Each KG explicitly delineates a target image’s core entities and their dependencies. We further introduce MMMG-Score to evaluate generated knowledge images. This metric combines factual fidelity, measured by graph-edit distance between KGs, with visual clarity assessment. Comprehensive evaluations of $21$ state-of-the-art text-to-image generation models expose serious reasoning deficits—low entity fidelity, weak relations, and clutter—with GPT-4o achieving an MMMG-Score of only $50. 20$, underscoring the benchmark’s difficulty. To spur further progress, we release FLUX-Reason (MMMG-Score of $34. 45$), an effective and open baseline that combines a reasoning LLM with diffusion models and is trained on $16, 000$ curated knowledge image–prompt pairs.

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AAAI Conference 2024 Conference Paper

Binding-Adaptive Diffusion Models for Structure-Based Drug Design

Zhilin Huang
Ling Yang
Zaixi Zhang
Xiangxin Zhou
Yu Bao
Xiawu Zheng
Yuwei Yang
Yu Wang

Structure-based drug design (SBDD) aims to generate 3D ligand molecules that bind to specific protein targets. Existing 3D deep generative models including diffusion models have shown great promise for SBDD. However, it is complex to capture the essential protein-ligand interactions exactly in 3D space for molecular generation. To address this problem, we propose a novel framework, namely Binding-Adaptive Diffusion Models (BindDM). In BindDM, we adaptively extract subcomplex, the essential part of binding sites responsible for protein-ligand interactions. Then the selected protein-ligand subcomplex is processed with SE(3)-equivariant neural networks, and transmitted back to each atom of the complex for augmenting the target-aware 3D molecule diffusion generation with binding interaction information. We iterate this hierarchical complex-subcomplex process with cross-hierarchy interaction node for adequately fusing global binding context between the complex and its corresponding subcomplex. Empirical studies on the CrossDocked2020 dataset show BindDM can generate molecules with more realistic 3D structures and higher binding affinities towards the protein targets, with up to -5.92 Avg. Vina Score, while maintaining proper molecular properties. Our code is available at https://github.com/YangLing0818/BindDM

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ICLR Conference 2024 Conference Paper

DecompOpt: Controllable and Decomposed Diffusion Models for Structure-based Molecular Optimization

Xiangxin Zhou
Xiwei Cheng
Yuwei Yang
Yu Bao
Liang Wang 0001
Quanquan Gu

Recently, 3D generative models have shown promising performances in structure-based drug design by learning to generate ligands given target binding sites. However, only modeling the target-ligand distribution can hardly fulfill one of the main goals in drug discovery -- designing novel ligands with desired properties, e.g., high binding affinity, easily synthesizable, etc. This challenge becomes particularly pronounced when the target-ligand pairs used for training do not align with these desired properties. Moreover, most existing methods aim at solving de novo design task, while many generative scenarios requiring flexible controllability, such as R-group optimization and scaffold hopping, have received little attention. In this work, we propose DecompOpt, a structure-based molecular optimization method based on a controllable and decomposed diffusion model. DecompOpt presents a new generation paradigm which combines optimization with conditional diffusion models to achieve desired properties while adhering to the molecular grammar. Additionally, DecompOpt offers a unified framework covering both de novo design and controllable generation. To achieve so, ligands are decomposed into substructures which allows fine-grained control and local optimization. Experiments show that DecompOpt can efficiently generate molecules with improved properties than strong de novo baselines, and demonstrate great potential in controllable generation tasks.

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ICML Conference 2023 Conference Paper

DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design

Jiaqi Guan
Xiangxin Zhou
Yuwei Yang
Yu Bao
Jian Peng 0001
Jianzhu Ma
Qiang Liu 0006
Liang Wang 0001

Designing 3D ligands within a target binding site is a fundamental task in drug discovery. Existing structured-based drug design methods treat all ligand atoms equally, which ignores different roles of atoms in the ligand for drug design and can be less efficient for exploring the large drug-like molecule space. In this paper, inspired by the convention in pharmaceutical practice, we decompose the ligand molecule into two parts, namely arms and scaffold, and propose a new diffusion model, DecompDiff, with decomposed priors over arms and scaffold. In order to facilitate the decomposed generation and improve the properties of the generated molecules, we incorporate both bond diffusion in the model and additional validity guidance in the sampling phase. Extensive experiments on CrossDocked2020 show that our approach achieves state-of-the-art performance in generating high-affinity molecules while maintaining proper molecular properties and conformational stability, with up to $-8. 39$ Avg. Vina Dock score and $24. 5%$ Success Rate. The code is provided at https: //github. com/bytedance/DecompDiff

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ICLR Conference 2021 Conference Paper

MARS: Markov Molecular Sampling for Multi-objective Drug Discovery

Yutong Xie 0007
Chence Shi
Hao Zhou 0012
Yuwei Yang
Weinan Zhang 0001
Yong Yu 0001
Lei Li 0005

Searching for novel molecules with desired chemical properties is crucial in drug discovery. Existing work focuses on developing neural models to generate either molecular sequences or chemical graphs. However, it remains a big challenge to find novel and diverse compounds satisfying several properties. In this paper, we propose MARS, a method for multi-objective drug molecule discovery. MARS is based on the idea of generating the chemical candidates by iteratively editing fragments of molecular graphs. To search for high-quality candidates, it employs Markov chain Monte Carlo sampling (MCMC) on molecules with an annealing scheme and an adaptive proposal. To further improve sample efficiency, MARS uses a graph neural network (GNN) to represent and select candidate edits, where the GNN is trained on-the-fly with samples from MCMC. Experiments show that MARS achieves state-of-the-art performance in various multi-objective settings where molecular bio-activity, drug-likeness, and synthesizability are considered. Remarkably, in the most challenging setting where all four objectives are simultaneously optimized, our approach outperforms previous methods significantly in comprehensive evaluations. The code is available at https://github.com/yutxie/mars.

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