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Oct, 2023;27 (5): 2297-2314.

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

Jiali Xie, Dan Meng, Yihao Li, Ruoyu Li, Ping Deng
Author Information
  1. Jiali Xie: College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. ORCID
  2. Dan Meng: College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
  3. Yihao Li: College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
  4. Ruoyu Li: College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
  5. Ping Deng: College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China. 100865@cqmu.edu.cn. ORCID
PMID: 36322341 DOI: 10.1007/s11030-022-10557-8

Abstract

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) > Cpd1 (- 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.

Keywords

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

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Grants

  1. cstc2019jcyj-msxmX0034/the Fundamental and Advanced Research Projects of Chongqing City

MeSH Term

Discoidin Domain Receptor 1
Receptor Protein-Tyrosine Kinases
Discoidin Domain Receptors
Receptors, Mitogen
Molecular Docking Simulation

Chemicals

Discoidin Domain Receptor 1
Receptor Protein-Tyrosine Kinases
Discoidin Domain Receptors
Receptors, Mitogen
Journal Article

Word Cloud

Created with Highcharts 10.0.0DDR1inhibitors1screeningdomainreceptortargetcrystalmolecularpotentialcomplexsystemsdynamicsbindingDiscoidinpromisingpulmonaryfibrosisIPFspecificitydockingassessmentstructuresidentifiedusingmodelvirtualfivehitsimulationsMM/PBSAstabilityCpd17ECNumber2710recentlyconsideredtherapeuticidiopathicHowevernonecurrentlydiscoveredincludedclinicalstudiesduelowdruggabilitylimitationsnecessitatingvariousapproachesdevelopnovelstudyassureundertakenfindwell-differentiatedstructure4CKRamongmanybestpharmacophoreChEMBLdatabasedonemoleculesSubsequentlycompoundvalidatedmethodsassesssystemligandBasedhydrogen-bondingoccupancyanalysisDDR1-Cpd2DDR1-Cpd17DDR1-Cpd18exhibitedsuperiorcomparedDDR1-Cpd1DDR-Cpd33Meanwhiletargetingdescending ordermolecules'freeenergies- 145820 kJ/mol > Cpd2- 131818 kJ/mol > Cpd18- 130692 kJ/mol > Cpd33- 129175 kJ/mol > Cpd1- 126103 kJ/molAmongCpd2Cpd18showedimprovedcharacteristicsindicatingmayresearchdevelopedhigh-hitrateeffectivemethodservestheoreticalguidefindingdevelopmenttherapeuticsVirtualdiscoidinbasedstructuralinhibitorIdiopathiccalculationsMolecularPharmacophoreStructure-based

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