title: Design of novel ligands of CDP-methylerythritol kinase by mimicking direct protein-protein and solvent-mediated interactions.
abstract: The methylerythritol 4-phosphate (MEP) pathway for the biosynthesis of the isoprenoid universal building blocks (isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP)) is present in most of human pathogens and is absent in animals, turning it into a promising therapeutic druggable pathway. Two different strategies, a pharmacophore-directed virtual screening and a protein-protein interaction (PPI)-mimicking cyclic peptide were used to search for compounds that bind to the PPI surface of the 4-(cytidine 5-diphospho)-2C-methyl-D-erythritol kinase (CMK), which catalyzes the fourth step of the MEP pathway. A significant part of the pharmacophore hypothesis used in this study was designed by mimicking water-mediated PPI relevant in the CMK homodimer complex stabilization. After database search and with the aid of docking and molecular dynamics (MD) simulations, a 7H-furo[3,2-g]chromen-7-one derivative and a cyclic peptide were chosen as candidates to be ligands of CMK. Their binding affinities were measured using surface plasmon resonance (SPR) technology.
authors.affiliation: Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E-08028 Barcelona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Giménez-Oya
authors.forename: Oscar
authors.initials: O
authors.lastname: Villacañas
authors.forename: Cristian
authors.initials: C
authors.lastname: Obiol-Pardo
authors.forename: Meritxell
authors.initials: M
authors.lastname: Antolin-Llovera
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
authors.forename: Santiago
authors.initials: S
authors.lastname: Imperial
mesh_terms: D015195:Drug Design; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012997:Solvents / Q000737:chemistry; D020349:Surface Plasmon Resonance
chemical_list: D029968:Escherichia coli Proteins; D008024:Ligands; D010456:Peptides, Cyclic; D012997:Solvents; D017853:Phosphotransferases (Alcohol Group Acceptor); C404502:IspE protein, E coli