Chi Xinglong, Chen Roufen, Yang Xinle, He Xinjun, Pan Zhichao, Yao Chenpeng, Peng Huilin, Yang Haiyan, Huang Wenhai, Chen Zhilu
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.
ACS Med Chem Lett. 2025 Mar 17;16(4):602-610. doi: 10.1021/acsmedchemlett.4c00634. eCollection 2025 Apr 10.
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.
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。
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