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基于3D结构的分子生成器的基准测试

Benchmarking 3D Structure-Based Molecule Generators.

作者信息

Sanjrani Natasha, Coupry Damien E, Pogány Peter, Palmer David S, Pickett Stephen D

机构信息

Department of Cheminformatics, Research Technologies, GSK, Gunnels Wood Road, Stevenage SG1 2NY, U.K.

Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.

出版信息

J Chem Inf Model. 2025 Aug 11;65(15):8006-8021. doi: 10.1021/acs.jcim.5c01020. Epub 2025 Jul 25.


DOI:10.1021/acs.jcim.5c01020
PMID:40711830
Abstract

To understand the benefits and drawbacks of 3D combinatorial and deep learning generators, a novel benchmark was created focusing on the recreation of important protein-ligand interactions and 3D ligand conformations. Using the BindingMOAD data set with a hold-out blind set, the sequential graph neural network generators, Pocket2Mol and PocketFlow, diffusion models, DiffSBDD and MolSnapper, and combinatorial genetic algorithms, AutoGrow4 and LigBuilderV3, were evaluated. It was discovered that deep learning methods fail to generate structurally valid molecules and 3D conformations, whereas combinatorial methods are slow and generate molecules that are prone to failing 2D MOSES filters. The results from this evaluation guide us toward improving deep learning structure-based generators by placing higher importance on structural validity, 3D ligand conformations, and recreation of important known active site interactions. This benchmark should be used to understand the limitations of future combinatorial and deep learning generators. The package is freely available under an Apache 2.0 license at github.com/gskcheminformatics/SBDD-benchmarking.

摘要

为了解三维组合生成器和深度学习生成器的优缺点,创建了一个新颖的基准测试,重点是重现重要的蛋白质-配体相互作用和三维配体构象。使用带有留出盲集的BindingMOAD数据集,对序列图神经网络生成器Pocket2Mol和PocketFlow、扩散模型DiffSBDD和MolSnapper以及组合遗传算法AutoGrow4和LigBuilderV3进行了评估。研究发现,深度学习方法无法生成结构有效的分子和三维构象,而组合方法速度较慢,生成的分子容易通不过二维MOSES过滤器。该评估结果指导我们通过更重视结构有效性、三维配体构象以及重现重要的已知活性位点相互作用来改进基于深度学习结构的生成器。此基准测试应用于了解未来组合生成器和深度学习生成器的局限性。该软件包在github.com/gskcheminformatics/SBDD-benchmarking上根据Apache 2.0许可免费提供。

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本文引用的文献

[1]
MolSnapper: Conditioning Diffusion for Structure-Based Drug Design.

J Chem Inf Model. 2025-5-12

[2]
DiffInt: A Diffusion Model for Structure-Based Drug Design with Explicit Hydrogen Bond Interaction Guidance.

J Chem Inf Model. 2025-1-13

[3]
Durian: A Comprehensive Benchmark for Structure-Based 3D Molecular Generation.

J Chem Inf Model. 2025-1-13

[4]
Structure-based drug design with equivariant diffusion models.

Nat Comput Sci. 2024-12

[5]
How Good are Current Pocket-Based 3D Generative Models?: The Benchmark Set and Evaluation of Protein Pocket-Based 3D Molecular Generative Models.

J Chem Inf Model. 2024-12-23

[6]
3D molecular generative framework for interaction-guided drug design.

Nat Commun. 2024-3-27

[7]
A dual diffusion model enables 3D molecule generation and lead optimization based on target pockets.

Nat Commun. 2024-3-26

[8]
PoseBusters: AI-based docking methods fail to generate physically valid poses or generalise to novel sequences.

Chem Sci. 2023-12-13

[9]
STAGAN: An approach for improve the stability of molecular graph generation based on generative adversarial networks.

Comput Biol Med. 2023-12

[10]
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.

Science. 2023-11-10

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