Design of novel ligands of CDP‐methylerythritol kinase by mimicking direct protein‐protein and solvent‐mediated interactions |
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Authors: | Victor Giménez‐Oya Óscar Villacañas Cristian Obiol‐Pardo Meritxell Antolin‐Llovera Jaime Rubio‐Martinez Santiago Imperial |
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Affiliation: | 1. Department de Bioquímica i Biología Molecular, Universitat de Barcelona (UB), Avda Diagonal 645, E‐08028 Barcelona, Spain;2. Department de Química Física, Universitat de Barcelona (UB) and the Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Martí i Franquès 1, E‐08028 Barcelona, Spain |
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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. Copyright © 2010 John Wiley & Sons, Ltd. |
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Keywords: | CMK MEP MVA solvent‐mediated interactions protein‐protein interactions molecular dynamics drug design cyclic peptide small molecules surface plasmon resonance |
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