Abstract
Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-d-ribose epimerase involved in cell wall synthesis in Mycobacterium tuberculosis and catalyzes the conversion of decaprenylphosphoryl ribose to decaprenylphosphoryl arabinose. DprE1 is a potential target against tuberculosis, including multidrug-resistant tuberculosis. We identified potential DprE1 inhibitors from the ChemDiv dataset through virtual screening based on pharmacophore and molecular docking. Thirty selected compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity prediction with the Discovery Studio software package. Two compounds were obtained as hits for inhibiting DprE1 activity in M. tuberculosis and are suitable for further in vitro and in vivo evaluation.
Highlights
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a contagious airborne disease of humans that is one of the top 10 causes of death worldwide and has even caused higher mortality than the hunan immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)since 2015
Decaprenylphosphoryl-β-D-ribose oxidase (DprE1) is the flavoprotein subunit of decaprenylphosphoryl-D-ribose epimerase, which is involved in cell wall synthesis and produces decaprenylphosphoryl arabinose (DPA), a unique sugar donor for biogenesis of the essential mycobacterial cell wall polysaccharides arabinogalactan and lipoarabinomannan [3]
DprE1 uses Flavin adenine dinucleotide (FAD) to oxidize decaprenylphosphoryl ribose (DPR) to a keto intermediate, which is reduced to DPA by DprE2 using the reduced form of nicotinamide adenine dinucleotide (NADH) as a cofactor [4,5]
Summary
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a contagious airborne disease of humans that is one of the top 10 causes of death worldwide and has even caused higher mortality than the hunan immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)since 2015. According to the World Health Organization, there were an estimated 10.4 million new TB cases and. People living with HIV accounted for 1.2 million (11%) of all new TB cases [1]. Due to the emergence of multidrug-resistant TB, extensively drug-resistant (XDR). DprE1 acts in concert with DprE2 to catalyze the two-step epimerization of decaprenylphosphoryl ribose (DPR) to DPA. DprE1 uses Flavin adenine dinucleotide (FAD) to oxidize DPR to a keto intermediate, which is reduced to DPA by DprE2 using the reduced form of nicotinamide adenine dinucleotide (NADH) as a cofactor [4,5]. Analysis of orthologs has revealed that DprE1 is essential for the growth of mycobacteria, making it a valuable target for drug development [5]
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