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  • Computational model of the E. coli MurD enzyme and in silico design of novel inhibitors of the Mur ligase family
    Perdih, Andrej, farmacevt ...
    The growing incidence of bacterial resistance to the available antibiotics renders the discovery of novel antibacterial agents imperative. An essential bacterial component, peptidoglycan, is ... traditionally an optimal target with respect to selective toxicity. In the peptidoglycan biosynthetic pathway, Murligases (MurC-MurF) catalyze the intracellular construction of its peptide moiety. MurD enzyme in particular catalyzes the incorporation of the D-Glu into the UMA precursor, coupled with concurrent ATP hydrolysis. In ourongoing research, a complex dynamical model ofthe E. coli MurD enzyme was derived. To begin, targeted molecular dynamics (TMD) simulations were performed to examine the ligands' UMA and ATP binding processes and gain insight into the closure of the C-terminal domain.An off-path simulation (OPS) technique was initiated for the energy evaluation of the TMD-generated pathwavs. A QM/MM molecular modeling approach was utilized to evaluate reaction pathways leading to tetrahedral intermediate formation-a frequent drug design starting point. Calculated models confirmed the expected reaction order, first taking place between the ATP and UMA, resulting in the acyl-phosphate intermediate, followed by the addition of the D-Glu, which most likely enters the enzyme reaction in its deprotonated form. Binding freeenergies calculated for a series of MurD D-Glu-based inhibitors and their rigid surrogates revealed nonpolar van der Waals interactions as the main driving force for the binding of these inhibitors. Based on the available structural data for the MurD and MurE enzymes, a virtual screening campaign was performed, resulting in the identification of a novel class of glutamic acid surrogates- benzene 1,3-dicarboxylic acid derivatives possessing dual MurD and MurE inhibitory activity. Subsequent design steps outlined 1,3-dicarboxylic acid derivatives with multiple Mur ligase (MurC- MurF) inhibition.
    Vir: Book of abstracts (Str. 286-287)
    Vrsta gradiva - prispevek na konferenci
    Leto - 2012
    Jezik - angleški
    COBISS.SI-ID - 5109530

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