title: Iron depletion strategy for targeted cancer therapy: utilizing the dual roles of neutrophil gelatinase-associated lipocalin protein.
abstract: Decreasing iron uptake and increasing iron efflux may result in cell death by oxidative inactivation of vital enzymes. Applying the dual function of neutrophil gelatinase-associated lipocalin (NGAL) could achieve the goal of iron depletion in the cancer cells. Tyr106, Lys125 or Lys134 was the key binding site for NGAL protein to sequester iron-chelating siderophores. In this study, we employed all bioactive peptides in peptide databank to dock with the siderophore-binding sites of NGAL protein by virtual screening. In addition, we performed molecular dynamics (MD) simulation to observe the molecular character and structural variation of ligand-protein interaction. Glu-Glu-Lys-Glu (EEKE), Glu-Glu-Asp-Cys-Lys (EEDCK), and Gly-Glu-Glu-Cys-Asp (GEECD) were selected preliminarily by rigorous scoring functions for further investigation. GEECD was excluded due to higher binding total energy than the others. Moreover, we also excluded EEKE due to larger influence to the stability of binding residues by the information of root mean square fluctuation (RMSF) and principal component analysis (PCA). Thus, we suggested that EEDCK was the potential bioactive peptide which had been proved to inhibit malignant cells for targeted cancer therapy. Graphical Abstract Perspective drug design of occupying the siderophore-binding sites of NGAL outside the cell temporarily by a potential short peptide until NGAL enters into the cell, and releasing the siderophore-binding sites inside the cell.
authors.affiliation: Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan.
authors.forename: Hsin-Chieh
authors.initials: HC
authors.lastname: Tang
authors.affiliation: Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chang
authors.affiliation: Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan. ycc929@mit.edu.|Human Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, 40402, Taiwan. ycc929@mit.edu.|Research Center for Chinese Medicine & Acupuncture, China Medical University, Taichung, 40402, Taiwan. ycc929@mit.edu.
authors.forename: Yu-Chian
authors.initials: YC
authors.lastname: Chen
mesh_terms: D000209:Acute-Phase Proteins / Q000737:chemistry* / Q000627:therapeutic use; D030562:Databases, Protein; D006801:Humans; D007501:Iron / Q000737:chemistry*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000737:chemistry* / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D007501:Iron
keywords: Iron depletion; Molecular dynamics (MD) simulation; Neutrophil gelatinase-associated lipocalin (NGAL); Peptide database; Principal component analysis (PCA); Root mean square fluctuation (RMSF)