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Jiaqi Guan

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12 papers

2 author rows

ICLR Conference 2025 Conference Paper

Group Ligands Docking to Protein Pockets

Jiaqi Guan
Jiahan Li
Xiangxin Zhou
Xingang Peng
Sheng Wang 0001
Yunan Luo
Jian Peng 0001
Jianzhu Ma

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 state-of-the-art performance on the PDBBind blind docking benchmark, demonstrating the effectiveness of our paradigm in enhancing molecular docking accuracy.

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ICLR Conference 2025 Conference Paper

Hotspot-Driven Peptide Design via Multi-Fragment Autoregressive Extension

Jiahan Li
Tong Chen
Shitong Luo
Chaoran Cheng
Jiaqi Guan
Ruihan Guo
Sheng Wang
Ge Liu

Peptides, short chains of amino acids, interact with target proteins, making them a unique class of protein-based therapeutics for treating human diseases. Recently, deep generative models have shown great promise in peptide generation. However, several challenges remain in designing effective peptide binders. First, not all residues contribute equally to peptide-target interactions. Second, the generated peptides must adopt valid geometries due to the constraints of peptide bonds. Third, realistic tasks for peptide drug development are still lacking. To address these challenges, we introduce PepHAR, a hot-spot-driven autoregressive generative model for designing peptides targeting specific proteins. Building on the observation that certain hot spot residues have higher interaction potentials, we first use an energy-based density model to fit and sample these key residues. Next, to ensure proper peptide geometry, we autoregressively extend peptide fragments by estimating dihedral angles between residue frames. Finally, we apply an optimization process to iteratively refine fragment assembly, ensuring correct peptide structures. By combining hot spot sampling with fragment-based extension, our approach enables \textit{de novo} peptide design tailored to a target protein and allows the incorporation of key hot spot residues into peptide scaffolds. Extensive experiments, including peptide design and peptide scaffold generation, demonstrate the strong potential of PepHAR in computational peptide binder design. The source code will be available at https://github.com/Ced3-han/PepHAR.

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ICLR Conference 2025 Conference Paper

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

Xiangxin Zhou
Yi Xiao
Haowei Lin
Xinheng He
Jiaqi Guan
Yang Wang 0103
Qiang Liu 0006
Feng Zhou

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.

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NeurIPS Conference 2024 Conference Paper

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

Xiangxin Zhou
Jiaqi Guan
Yijia Zhang
Xingang Peng
Liang Wang
Jianzhu Ma

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.

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ICLR Conference 2023 Conference Paper

3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction

Jiaqi Guan
Wesley Wei Qian
Xingang Peng
Yufeng Su
Jian Peng 0001
Jianzhu Ma

Rich data and powerful machine learning models allow us to design drugs for a specific protein target <em>in silico</em>. Recently, the inclusion of 3D structures during targeted drug design shows superior performance to other target-free models as the atomic interaction in the 3D space is explicitly modeled. However, current 3D target-aware models either rely on the voxelized atom densities or the autoregressive sampling process, which are not equivariant to rotation or easily violate geometric constraints resulting in unrealistic structures. In this work, we develop a 3D equivariant diffusion model to solve the above challenges. To achieve target-aware molecule design, our method learns a joint generative process of both continuous atom coordinates and categorical atom types with a SE(3)-equivariant network. Moreover, we show that our model can serve as an unsupervised feature extractor to estimate the binding affinity under proper parameterization, which provides an effective way for drug screening. To evaluate our model, we propose a comprehensive framework to evaluate the quality of sampled molecules from different dimensions. Empirical studies show our model could generate molecules with more realistic 3D structures and better affinities towards the protein targets, and improve binding affinity ranking and prediction without retraining.

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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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NeurIPS Conference 2023 Conference Paper

LinkerNet: Fragment Poses and Linker Co-Design with 3D Equivariant Diffusion

Jiaqi Guan
Xingang Peng
PeiQi Jiang
Yunan Luo
Jian Peng
Jianzhu Ma

Targeted protein degradation techniques, such as PROteolysis TArgeting Chimeras (PROTACs), have emerged as powerful tools for selectively removing disease-causing proteins. One challenging problem in this field is designing a linker to connect different molecular fragments to form a stable drug-candidate molecule. Existing models for linker design assume that the relative positions of the fragments are known, which may not be the case in real scenarios. In this work, we address a more general problem where the poses of the fragments are unknown in 3D space. We develop a 3D equivariant diffusion model that jointly learns the generative process of both fragment poses and the 3D structure of the linker. By viewing fragments as rigid bodies, we design a fragment pose prediction module inspired by the Newton-Euler equations in rigid body mechanics. Empirical studies on ZINC and PROTAC-DB datasets demonstrate that our model can generate chemically valid, synthetically-accessible, and low-energy molecules under both unconstrained and constrained generation settings.

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ICML Conference 2023 Conference Paper

MolDiff: Addressing the Atom-Bond Inconsistency Problem in 3D Molecule Diffusion Generation

Xingang Peng
Jiaqi Guan
Qiang Liu 0001
Jianzhu Ma

Deep generative models have recently achieved superior performance in 3D molecule generation. Most of them first generate atoms and then add chemical bonds based on the generated atoms in a post-processing manner. However, there might be no corresponding bond solution for the temporally generated atoms as their locations are generated without considering potential bonds. We define this problem as the atom-bond inconsistency problem and claim it is the main reason for current approaches to generating unrealistic 3D molecules. To overcome this problem, we propose a new diffusion model called MolDiff which can generate atoms and bonds simultaneously while still maintaining their consistency by explicitly modeling the dependence between their relationships. We evaluated the generation ability of our proposed model and the quality of the generated molecules using criteria related to both geometry and chemical properties. The empirical studies showed that our model outperforms previous approaches, achieving a three-fold improvement in success rate and generating molecules with significantly better quality.

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ICLR Conference 2022 Conference Paper

Energy-Inspired Molecular Conformation Optimization

Jiaqi Guan
Wesley Wei Qian
Qiang Liu 0001
Wei-Ying Ma
Jianzhu Ma
Jian Peng 0001

This paper studies an important problem in computational chemistry: predicting a molecule's spatial atom arrangements, or a molecular conformation. We propose a neural energy minimization formulation that casts the prediction problem into an unrolled optimization process, where a neural network is parametrized to learn the gradient fields of an implicit conformational energy landscape. Assuming different forms of the underlying potential energy function, we can not only reinterpret and unify many of the existing models but also derive new variants of SE(3)-equivariant neural networks in a principled manner. In our experiments, these new variants show superior performance in molecular conformation optimization comparing to existing SE(3)-equivariant neural networks. Moreover, our energy-inspired formulation is also suitable for molecular conformation generation, where we can generate more diverse and accurate conformers comparing to existing baselines.

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ICML Conference 2022 Conference Paper

Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets

Xingang Peng
Shitong Luo
Jiaqi Guan
Qi Xie 0004
Jian Peng 0001
Jianzhu Ma

Deep generative models have achieved tremendous success in designing novel drug molecules in recent years. A new thread of works have shown potential in advancing the specificity and success rate of in silico drug design by considering the structure of protein pockets. This setting posts fundamental computational challenges in sampling new chemical compounds that could satisfy multiple geometrical constraints imposed by pockets. Previous sampling algorithms either sample in the graph space or only consider the 3D coordinates of atoms while ignoring other detailed chemical structures such as bond types and functional groups. To address the challenge, we develop an E(3)-equivariant generative network composed of two modules: 1) a new graph neural network capturing both spatial and bonding relationships between atoms of the binding pockets and 2) a new efficient algorithm which samples new drug candidates conditioned on the pocket representations from a tractable distribution without relying on MCMC. Experimental results demonstrate that molecules sampled from Pocket2Mol achieve significantly better binding affinity and other drug properties such as drug-likeness and synthetic accessibility.

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NeurIPS Conference 2021 Conference Paper

A 3D Generative Model for Structure-Based Drug Design

Shitong Luo
Jiaqi Guan
Jianzhu Ma
Jian Peng

We study a fundamental problem in structure-based drug design --- generating molecules that bind to specific protein binding sites. While we have witnessed the great success of deep generative models in drug design, the existing methods are mostly string-based or graph-based. They are limited by the lack of spatial information and thus unable to be applied to structure-based design tasks. Particularly, such models have no or little knowledge of how molecules interact with their target proteins exactly in 3D space. In this paper, we propose a 3D generative model that generates molecules given a designated 3D protein binding site. Specifically, given a binding site as the 3D context, our model estimates the probability density of atom's occurrences in 3D space --- positions that are more likely to have atoms will be assigned higher probability. To generate 3D molecules, we propose an auto-regressive sampling scheme --- atoms are sampled sequentially from the learned distribution until there is no room for new atoms. Combined with this sampling scheme, our model can generate valid and diverse molecules, which could be applicable to various structure-based molecular design tasks such as molecule sampling and linker design. Experimental results demonstrate that molecules sampled from our model exhibit high binding affinity to specific targets and good drug properties such as drug-likeness even if the model is not explicitly optimized for them.

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IJCAI Conference 2018 Conference Paper

Energy-efficient Amortized Inference with Cascaded Deep Classifiers

Jiaqi Guan
Yang Liu
Qiang Liu
Jian Peng

Deep neural networks have been remarkable successful in various AI tasks but often cast high computation and energy cost for energy-constrained applications such as mobile sensing. We address this problem by proposing a novel framework that optimizes the prediction accuracy and energy cost simultaneously, thus enabling effective cost-accuracy trade-off at test time. In our framework, each data instance is pushed into a cascade of deep neural networks with increasing sizes, and a selection module is used to sequentially determine when a sufficiently accurate classifier can be used for this data instance. The cascade of neural networks and the selection module are jointly trained in an end-to-end fashion by the REINFORCE algorithm to optimize a trade-off between the computational cost and the predictive accuracy. Our method is able to simultaneously improve the accuracy and efficiency by learning to assign easy instances to fast yet sufficiently accurate classifiers to save computation and energy cost, while assigning harder instances to deeper and more powerful classifiers to ensure satisfiable accuracy. Moreover, we demonstrate our method's effectiveness with extensive experiments on CIFAR-10/100, ImageNet32x32 and original ImageNet dataset.

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