文献检索文档翻译深度研究
Suppr Zotero 插件Zotero 插件
邀请有礼套餐&价格历史记录

新学期,新优惠

限时优惠:9月1日-9月22日

30天高级会员仅需29元

1天体验卡首发特惠仅需5.99元

了解详情
不再提醒
插件&应用
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
高级版
套餐订阅购买积分包
AI 工具
文献检索文档翻译深度研究
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利:CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2025

通过混合虚拟筛选流程、生物学评估和分子动力学模拟发现新型DDR1抑制剂

Discovery of Novel DDR1 Inhibitors through a Hybrid Virtual Screening Pipeline, Biological Evaluation and Molecular Dynamics Simulations.

作者信息

Chi Xinglong, Chen Roufen, Yang Xinle, He Xinjun, Pan Zhichao, Yao Chenpeng, Peng Huilin, Yang Haiyan, Huang Wenhai, Chen Zhilu

机构信息

Department of Hematology, Tongde Hospital of Zhejiang Province, No. 234, Gucui Road, Hangzhou 310012, Zhejiang, P.R. China.

Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, P.R. China.

出版信息

ACS Med Chem Lett. 2025 Mar 17;16(4):602-610. doi: 10.1021/acsmedchemlett.4c00634. eCollection 2025 Apr 10.


DOI:10.1021/acsmedchemlett.4c00634
PMID:40236534
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11995236/
Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy with limited therapeutic options for many patients. Discoidin domain receptor 1 (DDR1), a transmembrane tyrosine kinase receptor, has been implicated in AML progression and represents a promising therapeutic target. In this study, we employed a hybrid virtual screening workflow that integrates deep learning-based binding affinity predictions with molecular docking techniques to identify potential DDR1 inhibitors. A multistage screening process involving PSICHIC, KarmaDock, Vina-GPU, and similarity-based scoring was conducted, leading to the selection of seven candidate compounds. The biological evaluation identified Compound 4 as a novel DDR1 inhibitor, demonstrating significant DDR1 inhibitory activity with an IC of 46.16 nM and a 99.86% inhibition rate against Z-138 cells at 10 μM. Molecular dynamics simulations and binding free energy calculations further validated the stability and strong binding interactions of Compound 4 with DDR1. This study highlights the utility of combining deep learning models with traditional molecular docking techniques to accelerate the discovery of potent and selective DDR1 inhibitors. The identified compounds hold promise for further development as targeted therapies for AML.

摘要

急性髓系白血病(AML)是一种异质性造血恶性肿瘤,许多患者的治疗选择有限。盘状结构域受体1(DDR1)是一种跨膜酪氨酸激酶受体,与AML进展有关,是一个有前景的治疗靶点。在本研究中,我们采用了一种混合虚拟筛选工作流程,将基于深度学习的结合亲和力预测与分子对接技术相结合,以识别潜在的DDR1抑制剂。我们进行了一个包括PSICHIC、KarmaDock、Vina-GPU和基于相似性评分的多阶段筛选过程,最终选择了7种候选化合物。生物学评估确定化合物4为一种新型DDR1抑制剂,在10 μM浓度下对Z-138细胞显示出显著的DDR1抑制活性,IC为46.16 nM,抑制率为99.86%。分子动力学模拟和结合自由能计算进一步验证了化合物4与DDR1的稳定性和强结合相互作用。本研究强调了将深度学习模型与传统分子对接技术相结合在加速发现强效和选择性DDR1抑制剂方面的实用性。所鉴定的化合物有望作为AML的靶向治疗药物进一步开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/e69c79332c8f/ml4c00634_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/382416d58cf9/ml4c00634_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/30dc467b3985/ml4c00634_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/60be5eaa492b/ml4c00634_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/b1ffd5cb33aa/ml4c00634_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/98b263c6fb74/ml4c00634_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/99738efb0418/ml4c00634_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/4252979d220f/ml4c00634_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/f2202284ed97/ml4c00634_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/e69c79332c8f/ml4c00634_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/382416d58cf9/ml4c00634_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/30dc467b3985/ml4c00634_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/60be5eaa492b/ml4c00634_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/b1ffd5cb33aa/ml4c00634_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/98b263c6fb74/ml4c00634_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/99738efb0418/ml4c00634_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/4252979d220f/ml4c00634_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/f2202284ed97/ml4c00634_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/efff/11995236/e69c79332c8f/ml4c00634_0009.jpg

相似文献

[1]
Discovery of Novel DDR1 Inhibitors through a Hybrid Virtual Screening Pipeline, Biological Evaluation and Molecular Dynamics Simulations.

ACS Med Chem Lett. 2025-3-17

[2]
Identification of novel discoidin domain receptor 1 (DDR1) inhibitors using E-pharmacophore modeling, structure-based virtual screening, molecular dynamics simulation and MM-GBSA approaches.

Comput Biol Med. 2022-3

[3]
Virtual screening for potential discoidin domain receptor 1 (DDR1) inhibitors based on structural assessment.

Mol Divers. 2023-10

[4]
Identification of DDR1 Inhibitors from Marine Compound Library Based on Pharmacophore Model and Scaffold Hopping.

Int J Mol Sci. 2025-1-27

[5]
From pixels to druggable leads: A CADD strategy for the design and synthesis of potent DDR1 inhibitors.

Comput Methods Programs Biomed. 2024-9

[6]
Discovery of Pyrazolo[3,4-]pyridazinone Derivatives as Selective DDR1 Inhibitors via Deep Learning Based Design, Synthesis, and Biological Evaluation.

J Med Chem. 2022-1-13

[7]
Identification of Ureidocoumarin-Based Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors via Drug Repurposing Approach, Biological Evaluation, and In Silico Studies.

Pharmaceuticals (Basel). 2024-3-27

[8]
Discovery of 4-amino-1H-pyrazolo[3,4-d]pyrimidin derivatives as novel discoidin domain receptor 1 (DDR1) inhibitors.

Bioorg Med Chem. 2021-1-1

[9]
Identification of novel inhibitors of DDR1 against idiopathic pulmonary fibrosis by integrative transcriptome meta-analysis, computational and experimental screening.

Mol Biosyst. 2016-4-26

[10]
Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib.

Eur J Pharmacol. 2008-12-3

本文引用的文献

[1]
EvaluationMaster: A GUI Tool for Structure-Based Virtual Screening Evaluation Analysis and Decision-Making Support.

J Chem Inf Model. 2025-1-13

[2]
A head-to-head comparison of MM/PBSA and MM/GBSA in predicting binding affinities for the CB cannabinoid ligands.

J Mol Model. 2024-10-31

[3]
MedChemExpress compounds prevent neuraminidase N1 physics- and knowledge-based methods.

RSC Adv. 2024-6-12

[4]
DDR1-targeted therapies: current limitations and future potential.

Drug Discov Today. 2024-5

[5]
Efficient and accurate large library ligand docking with KarmaDock.

Nat Comput Sci. 2023-9

[6]
From intuition to AI: evolution of small molecule representations in drug discovery.

Brief Bioinform. 2023-11-22

[7]
The ChEMBL Database in 2023: a drug discovery platform spanning multiple bioactivity data types and time periods.

Nucleic Acids Res. 2024-1-5

[8]
PLANET: A Multi-objective Graph Neural Network Model for Protein-Ligand Binding Affinity Prediction.

J Chem Inf Model. 2024-4-8

[9]
Using ChEMBL to Complement Schistosome Drug Discovery.

Pharmaceutics. 2023-4-28

[10]
Therapies for acute myeloid leukemia in patients ineligible for standard induction chemotherapy: a systematic review.

Future Oncol. 2023-4

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

推荐工具

医学文档翻译智能文献检索