Molecule Generation for Target Protein Binding with Hierarchical Consistency Diffusion Model

• URL: http://arxiv.org/abs/2503.00975v1
• Date: Sun, 02 Mar 2025 17:54:30 GMT
• Title: Molecule Generation for Target Protein Binding with Hierarchical Consistency Diffusion Model
• Authors: Guanlue Li, Chenran Jiang, Ziqi Gao, Yu Liu, Chenyang Liu, Jiean Chen, Yong Huang, Jia Li,
• Abstract summary: Atom-Motif Consistency Diffusion Model (AMDiff) is a hierarchical diffusion architecture that integrates both atom- and motif-level views of molecules.<n>Compared to existing approaches, AMDiff exhibits superior validity and novelty in generating molecules tailored to fit various protein pockets.
• Score: 17.885767456439215
• License: http://arxiv.org/licenses/nonexclusive-distrib/1.0/
• Abstract: 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 for 3D molecular generation, current methods often struggle with validity and reliability. To address these issues, we develop the Atom-Motif Consistency Diffusion Model (AMDiff), utilizing a joint-training paradigm for multi-view learning. This model features a hierarchical diffusion architecture that integrates both atom- and motif-level views of molecules, allowing for comprehensive exploration of complementary information. By leveraging classifier-free guidance and incorporating binding site features as conditional inputs, AMDiff ensures robust molecule generation across diverse targets. Compared to existing approaches, AMDiff exhibits superior validity and novelty in generating molecules tailored to fit various protein pockets. Case studies targeting protein kinases, including Anaplastic Lymphoma Kinase (ALK) and Cyclin-dependent kinase 4 (CDK4), demonstrate the model's capability in structure-based de novo drug design. Overall, AMDiff bridges the gap between atom-view and motif-view drug discovery and speeds up the process of target-aware molecular generation.

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