title: Design of an interface peptide as new inhibitor of human glucose-6-phosphate dehydrogenase.
abstract: Glucose-6-phosphate dehydrogenase (G6PDH) is an essential enzyme involved in the first reaction of the oxidative branch of the pentose phosphate pathway (PPP). Recently, G6PDH was suggested as a novel target protein for cancer therapy as one of the final products of the PPP, ribose-5-phosphate, is necessary for nucleic acid synthesis and tumor progression. After analyzing the protein-protein interface of the crystal structure of human G6PDH by means of molecular dynamics simulations, we designed six interface peptides based on the natural sequence of the protein. The three most promising peptides, as predicted by binding free energy calculations, were synthesized and one of them was confirmed as a novel inhibitor of human G6PDH in experimental assays. Together, the active peptide found and its suggested binding mode proposes a new strategy for inhibiting this enzyme and should aid the further design of novel, potent and non-peptidic G6PDH inhibitors.
authors.affiliation: Departament de Química Física, University of Barcelona and Institut de Recerca en Química Teòrica i Computacional (XRQTC). Martí i Franquès 1, 08028 Barcelona, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Obiol-Pardo
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina, University of Barcelona (IBUB) and IDIBAPS-Hospital Clinic, Barcelona, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Alcarraz-Vizán
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina, University of Barcelona (IBUB) and IDIBAPS-Hospital Clinic, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Díaz-Moralli
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Institut de Biomedicina, University of Barcelona (IBUB) and IDIBAPS-Hospital Clinic, Barcelona, Spain. Electronic address: martacascante@ub.edu.
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.affiliation: Departament de Química Física, University of Barcelona and Institut de Recerca en Química Teòrica i Computacional (XRQTC). Martí i Franquès 1, 08028 Barcelona, Spain. Electronic address: jaime.rubio@ub.edu.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D005954:Glucosephosphate Dehydrogenase
keywords: Cancer; Glucose-6-phosphate dehydrogenase; Interface peptides; MMPBSA; Molecular modeling