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.

Characterization of Domiphen Bromide as a New Fast-Acting Antiplasmodial Agent Inhibiting the Apicoplastidic Methyl Erythritol Phosphate Pathway

“…Abbreviations: pyruvate (Pyr), glyceraldehyde 3-phosphate (G3P), 1-deoxy-D-xylulose 5-phosphate (DXP), DXP synthase (DXS), DXP reductoisomerase (DXR), 2- C -methyl-D-erythritol 4-phosphate (MEP), MEP cytidylyltransferase (CMS), 4-diphosphocytidyl-2- C -methylerythritol (CDP-ME), CDP-ME kinase (CMK), CDP-ME 2-phosphate (CDP-MEP), 2- C -methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP), MEcPP synthase (MCS), ( E )-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), HMB-PP synthase (HDS), HMB-PP reductase (HDR), dimethylallyl pyrophosphate (DMAPP), isopentenyl pyrophosphate (IPP). Adapted from the scheme with permission from [ 18 ] Copyright 2010 John Wiley and Sons.…”

“…Pharmaceutics 2022, 14, x FOR PEER REVIEW 3 of 14 methyl-D-erythritol 2,4-cyclodiphosphate (MEcPP), MEcPP synthase (MCS), (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), HMB-PP synthase (HDS), HMB-PP reductase (HDR), dimethylallyl pyrophosphate (DMAPP), isopentenyl pyrophosphate (IPP). Adapted from the scheme with permission from [18] Copyright 2010 John Wiley and Sons.…”

Computational close up on protein–protein interactions: how to unravel the invisible using molecular dynamics simulations?

“…For the design of novel ligands binding CDP‐methylerythritol kinase (CMK), an interesting strategy was developed by Gimenez‐Oya et al: Instead of targeting the ATP‐binding site, the authors aimed at inhibiting the CMK homodimer complex stabilization. The protein–protein and solvent‐mediated interactions were identified by MD simulations and led to the construction of a pharmacophore model for the discovery of novel inhibitors by virtual screening.…”