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

作者全名："Xie, Jiali; Meng, Dan; Li, Yihao; Li, Ruoyu; Deng, Ping"

作者地址："[Xie, Jiali; Meng, Dan; Li, Yihao; Li, Ruoyu; Deng, Ping] Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China; [Xie, Jiali; Meng, Dan; Li, Yihao; Deng, Ping] Chongqing Res Ctr Pharmaceut Engn, Chongqing 400016, Peoples R China; [Xie, Jiali; Meng, Dan; Deng, Ping] Chongqing Key Res Lab Qual Evaluat & Safety Res A, Chongqing 400016, Peoples R China"

通信作者："Deng, P (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China.; Deng, P (通讯作者)，Chongqing Res Ctr Pharmaceut Engn, Chongqing 400016, Peoples R China.; Deng, P (通讯作者)，Chongqing Key Res Lab Qual Evaluat & Safety Res A, Chongqing 400016, Peoples R China."

来源：MOLECULAR DIVERSITY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000877982900002

JCR分区：Q2

影响因子：3.8

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Discoidin domain receptor 1 inhibitor; Idiopathic pulmonary fibrosis; Structure-based virtual screening; Pharmacophore model; Molecular dynamics; MM/PBSA calculations

摘要："Discoidin domain receptor 1 (DDR1) (EC Number 2.7.10.1) has recently been considered as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF). However, none of the currently discovered DDR1 inhibitors have been included in clinical studies due to low target specificity or druggability limitations, necessitating various approaches to develop novel DDR1 inhibitors. In this study, to assure target specificity, a docking assessment of the DDR1 crystal structures was undertaken to find the well-differentiated crystal structure, and 4CKR was identified among many crystal structures. Then, using the best pharmacophore model and molecular docking, virtual screening of the ChEMBL database was done, and five potential molecules were identified as promising inhibitors of DDR1. Subsequently, all hit compound complex systems were validated using molecular dynamics simulations and MM/PBSA methods to assess the stability of the system after ligand binding to DDR1. Based on molecular dynamics simulations and hydrogen-bonding occupancy analysis, the DDR1-Cpd2, DDR1-Cpd17, and DDR1-Cpd18 complex systems exhibited superior stability compared to the DDR1-Cpd1 and DDR-Cpd33 complex systems. Meanwhile, when targeting DDR1, the descending order of the five hit molecules' binding free energies was Cpd17 (- 145.820 kJ/mol)>Cpd2 (- 131.818 kJ/mol)> Cpd18 (- 130.692 kJ/mol)>Cpd33 (- 129.175 kJ/mol)> Cpdl (- 126.103 kJ/mol). Among them, Cpd2, Cpd17, and Cpd18 showed improved binding characteristics, indicating that they may be potential DDR1 inhibitors. In this research, we developed a high-hit rate, effective screening method that serves as a theoretical guide for finding DDR1 inhibitors for the development of IPF therapeutics. [GRAPHICS] ."

基金机构：Fundamental and Advanced Research Projects of Chongqing City [cstc2019jcyj-msxmX0034]

基金资助正文：This research was funded by the Fundamental and Advanced Research Projects of Chongqing City (cstc2019jcyj-msxmX0034).