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Diffusion models offer a powerful means of capturing the manifold of realistic protein structures, enabling rapid design for protein engineering tasks. However, existing approaches observe critical failure modes when precise constraints are…

Biomolecules · Quantitative Biology 2026-03-27 Jacob K. Christopher , Austin Seamann , Jingyi Cui , Sagar Khare , Ferdinando Fioretto

The cornerstone of computational drug design is the calculation of binding affinity between two biological counterparts, especially a chemical compound, i.e., a ligand, and a protein. Predicting the strength of protein-ligand binding with…

Biomolecules · Quantitative Biology 2019-12-04 Yanjun Li , Mohammad A. Rezaei , Chenglong Li , Xiaolin Li , Dapeng Wu

Structure-based drug design aims at generating high affinity ligands with prior knowledge of 3D target structures. Existing methods either use conditional generative model to learn the distribution of 3D ligands given target binding sites,…

Biomolecules · Quantitative Biology 2024-03-18 Yuwei Yang , Siqi Ouyang , Xueyu Hu , Mingyue Zheng , Hao Zhou , Lei Li

Developing bioactive molecules remains a central, time- and cost-heavy challenge in drug discovery, particularly for novel targets lacking structural or functional data. Pharmacophore modeling presents an alternative for capturing the key…

Machine Learning · Computer Science 2025-05-16 Amira Alakhdar , Barnabas Poczos , Newell Washburn

Advances in deep generative models shed light on de novo molecule generation with desired properties. However, molecule generation targeted for dual protein targets still faces formidable challenges including protein 3D structure data…

Currently, the field of structure-based drug design is dominated by three main types of algorithms: search-based algorithms, deep generative models, and reinforcement learning. While existing works have typically focused on comparing models…

Machine Learning · Computer Science 2026-01-22 Kangyu Zheng , Kai Zhang , Jiale Tan , Xuehan Chen , Yingzhou Lu , Zaixi Zhang , Lichao Sun , Marinka Zitnik , Tianfan Fu , Zhiding Liang

Diffusion models have emerged as powerful tools for molecular generation, particularly in the context of 3D molecular structures. Inspired by non-equilibrium statistical physics, these models can generate 3D molecular structures with…

Chemical Physics · Physics 2025-05-16 Amira Alakhdar , Barnabas Poczos , Newell Washburn

Structure-based drug design (SBDD) leverages the 3D structure of biomolecular targets to guide the creation of new therapeutic agents. Recent advances in generative models, including diffusion models and geometric deep learning, have…

Biomolecules · Quantitative Biology 2025-01-28 Ali Khodabandeh Yalabadi , Mehdi Yazdani-Jahromi , Ozlem Ozmen Garibay

Generating ligand molecules for specific protein targets, known as structure-based drug design, is a fundamental problem in therapeutics development and biological discovery. Recently, target-aware generative models, especially diffusion…

Biomolecules · Quantitative Biology 2024-10-29 Siyi Gu , Minkai Xu , Alexander Powers , Weili Nie , Tomas Geffner , Karsten Kreis , Jure Leskovec , Arash Vahdat , Stefano Ermon

Molecule generation, especially generating 3D molecular geometries from scratch (i.e., 3D \textit{de novo} generation), has become a fundamental task in drug designs. Existing diffusion-based 3D molecule generation methods could suffer from…

Machine Learning · Computer Science 2022-09-14 Lei Huang , Hengtong Zhang , Tingyang Xu , Ka-Chun Wong

Proteins in complex with small molecule ligands represent the core of structure-based drug discovery. However, three-dimensional representations are absent from most deep-learning-based generative models. We here present a graph-based…

Biomolecules · Quantitative Biology 2022-04-07 Seung-gu Kang , Jeffrey K. Weber , Joseph A. Morrone , Leili Zhang , Tien Huynh , Wendy D. Cornell

Effective generation of molecular structures, or new chemical entities, that bind to target proteins is crucial for lead identification and optimization in drug discovery. Despite advancements in atom- and motif-wise deep learning models…

Machine Learning · Computer Science 2025-03-04 Guanlue Li , Chenran Jiang , Ziqi Gao , Yu Liu , Chenyang Liu , Jiean Chen , Yong Huang , Jia Li

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…

Biomolecules · Quantitative Biology 2025-03-07 Xiangxin Zhou , Yi Xiao , Haowei Lin , Xinheng He , Jiaqi Guan , Yang Wang , Qiang Liu , Feng Zhou , Liang Wang , Jianzhu Ma

Structure-based drug design (SBDD) leverages the three-dimensional geometry of proteins to identify potential drug candidates. Traditional approaches, rooted in physicochemical modeling and domain expertise, are often resource-intensive.…

Quantitative Methods · Quantitative Biology 2024-11-19 Zaixi Zhang , Jiaxian Yan , Yining Huang , Qi Liu , Enhong Chen , Mengdi Wang , Marinka Zitnik

Recent advances in Structure-based Drug Design (SBDD) have leveraged generative models for 3D molecular generation, predominantly evaluating model performance by binding affinity to target proteins. However, practical drug discovery…

A fundamental problem in drug discovery is to design molecules that bind to specific proteins. To tackle this problem using machine learning methods, here we propose a novel and effective framework, known as GraphBP, to generate 3D…

Biomolecules · Quantitative Biology 2022-05-31 Meng Liu , Youzhi Luo , Kanji Uchino , Koji Maruhashi , Shuiwang Ji

Structure-based drug discovery (SBDD) is a systematic scientific process that develops new drugs by leveraging the detailed physical structure of the target protein. Recent advancements in pre-trained models for biomolecules have…

Machine Learning · Computer Science 2025-03-07 Yiheng Zhu , Mingyang Li , Junlong Liu , Kun Fu , Jiansheng Wu , Qiuyi Li , Mingze Yin , Jieping Ye , Jian Wu , Zheng Wang

Identifying drug-target interactions is essential for developing effective therapeutics. Binding affinity quantifies these interactions, and traditional approaches rely on computationally intensive 3D structural data. In contrast, language…

Quantitative Methods · Quantitative Biology 2024-11-08 Radheesh Sharma Meda , Amir Barati Farimani

Deep generative models are rapidly advancing structure-based drug design, offering substantial promise for generating small molecule ligands that bind to specific protein targets. However, most current approaches assume a rigid protein…

Biomolecules · Quantitative Biology 2025-11-19 Xinzhe Zheng , Shiyu Jiang , Gustavo Seabra , Chenglong Li , Yanjun Li

The design of target-specific molecules such as small molecules, peptides, and antibodies is vital for biological research and drug discovery. Existing generative methods are restricted to single-domain molecules, failing to address…

Machine Learning · Computer Science 2025-05-27 Xiangzhe Kong , Zishen Zhang , Ziting Zhang , Rui Jiao , Jianzhu Ma , Wenbing Huang , Kai Liu , Yang Liu