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双扩散模型能够基于靶口袋进行 3D 分子生成和先导化合物优化。

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

机构信息

City University of Hong Kong, Hong Kong, SAR, China.

Tencent AI Lab, Shenzhen, China.

出版信息

Nat Commun. 2024 Mar 26;15(1):2657. doi: 10.1038/s41467-024-46569-1.


DOI:10.1038/s41467-024-46569-1
PMID:38531837
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10965937/
Abstract

Structure-based generative chemistry is essential in computer-aided drug discovery by exploring a vast chemical space to design ligands with high binding affinity for targets. However, traditional in silico methods are limited by computational inefficiency, while machine learning approaches face bottlenecks due to auto-regressive sampling. To address these concerns, we have developed a conditional deep generative model, PMDM, for 3D molecule generation fitting specified targets. PMDM consists of a conditional equivariant diffusion model with both local and global molecular dynamics, enabling PMDM to consider the conditioned protein information to generate molecules efficiently. The comprehensive experiments indicate that PMDM outperforms baseline models across multiple evaluation metrics. To evaluate the applications of PMDM under real drug design scenarios, we conduct lead compound optimization for SARS-CoV-2 main protease (M) and Cyclin-dependent Kinase 2 (CDK2), respectively. The selected lead optimization molecules are synthesized and evaluated for their in-vitro activities against CDK2, displaying improved CDK2 activity.

摘要

基于结构的生成化学在计算机辅助药物发现中至关重要,它可以探索广阔的化学空间,设计与靶标具有高结合亲和力的配体。然而,传统的计算方法受到计算效率的限制,而机器学习方法由于自回归采样而面临瓶颈。为了解决这些问题,我们开发了一种条件深度生成模型 PMDM,用于根据指定的靶标生成 3D 分子。PMDM 由具有局部和全局分子动力学的条件等变扩散模型组成,使 PMDM 能够考虑条件化的蛋白质信息,从而有效地生成分子。全面的实验表明,PMDM 在多个评估指标上均优于基准模型。为了评估 PMDM 在实际药物设计场景下的应用,我们分别针对严重急性呼吸系统综合征冠状病毒 2 主蛋白酶(M)和细胞周期蛋白依赖性激酶 2(CDK2)进行先导化合物优化。选择的先导优化分子进行了合成,并评估了它们对 CDK2 的体外活性,显示出改善的 CDK2 活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/dbfecf74dc82/41467_2024_46569_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/7d06ebb513ad/41467_2024_46569_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/f07329308bd7/41467_2024_46569_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/57aaa2340a63/41467_2024_46569_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/17e3dfa38c19/41467_2024_46569_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/d18884c4d46e/41467_2024_46569_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/dbfecf74dc82/41467_2024_46569_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/7d06ebb513ad/41467_2024_46569_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/f07329308bd7/41467_2024_46569_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/57aaa2340a63/41467_2024_46569_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/17e3dfa38c19/41467_2024_46569_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/d18884c4d46e/41467_2024_46569_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bb25/10965937/dbfecf74dc82/41467_2024_46569_Fig6_HTML.jpg

相似文献

[1]
A dual diffusion model enables 3D molecule generation and lead optimization based on target pockets.

Nat Commun. 2024-3-26

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[9]
Generative adversarial network (GAN) model-based design of potent SARS-CoV-2 M inhibitors using the electron density of ligands and 3D binding pockets: insights from molecular docking, dynamics simulation, and MM-GBSA analysis.

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[10]
De novo design and bioactivity prediction of SARS-CoV-2 main protease inhibitors using recurrent neural network-based transfer learning.

BMC Chem. 2021-2-2

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[2]
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[3]
Target-aware 3D molecular generation based on guided equivariant diffusion.

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[4]
Optimizing drug design by merging generative AI with a physics-based active learning framework.

Commun Chem. 2025-8-8

[5]
Generative artificial intelligence based models optimization towards molecule design enhancement.

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[6]
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[7]
A diffusion model for universal medical image enhancement.

Commun Med (Lond). 2025-7-15

[8]
Generative Deep Learning for de Novo Drug Design─A Chemical Space Odyssey.

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[9]
In-silico 3D molecular editing through physics-informed and preference-aligned generative foundation models.

Nat Commun. 2025-7-1

[10]
A genotype-to-drug diffusion model for generation of tailored anti-cancer small molecules.

Nat Commun. 2025-7-1

本文引用的文献

[1]
UCSF ChimeraX: Tools for structure building and analysis.

Protein Sci. 2023-11

[2]
Accelerated Discovery of Macrocyclic CDK2 Inhibitor QR-6401 by Generative Models and Structure-Based Drug Design.

ACS Med Chem Lett. 2023-2-8

[3]
Discovery of 5,7-Dihydro-6-pyrrolo[2,3-]pyrimidin-6-ones as Highly Selective CDK2 Inhibitors.

ACS Med Chem Lett. 2022-10-6

[4]
Generating 3D molecules conditional on receptor binding sites with deep generative models.

Chem Sci. 2022-2-7

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Inverse design of 3d molecular structures with conditional generative neural networks.

Nat Commun. 2022-2-21

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Structure-based drug design using 3D deep generative models.

Chem Sci. 2021-9-9

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De Novo Molecule Design Through the Molecular Generative Model Conditioned by 3D Information of Protein Binding Sites.

J Chem Inf Model. 2021-7-26

[8]
Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations.

ACS Cent Sci. 2021-3-24

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J Chem Inf Model. 2020-9-28

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