title: Structure-based design of diverse inhibitors of Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase: combined molecular docking, dynamic simulation, and biological activity.
abstract: Persistent nature of Mycobacterium tuberculosis is one of the major factors which make the drug development process monotonous against this organism. The highly lipophilic cell wall, which constituting outer mycolic acid and inner peptidoglycan layers, acts as a barrier for the drugs to enter the bacteria. The rigidity of the cell wall is imparted by the peptidoglycan layer, which is covalently linked to mycolic acid by arabinogalactan. Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) serves as the starting material in the biosynthesis of this peptidoglycan layers. This UDP-GlcNAc is synthesized by N-acetylglucosamine-1-phosphate uridyltransferase (GlmU(Mtb)), a bi-functional enzyme with two functional sites, acetyltransferase site and uridyltransferase site. Here, we report design and screening of nine inhibitors against UTP and NAcGlc-1-P of uridyltransferase active site of glmU(Mtb). Compound 4 was showing good inhibition and was selected for further analysis. The isothermal titration calorimetry (ITC) experiments showed the binding energy pattern of compound 4 to the uridyltransferase active site is similar to that of substrate UTP. In silico molecular dynamics (MD) simulation studies, for compound 4, carried out for 10 ns showed the protein-compound complex to be stable throughout the simulation with relative rmsd in acceptable range. Hence, these compounds can serve as a starting point in the drug discovery processes against Mycobacterium tuberculosis.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Soni
authors.forename: Priyanka
authors.initials: P
authors.lastname: Suryadevara
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Santhosh
authors.initials: S
authors.lastname: Kumar
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Nandicoori
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000201:enzymology; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013864:Thioglycolates / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry*; D014544:Uridine Triphosphate / Q000737:chemistry*
chemical_list: C000606089:((4-methyl(1,2,4)triazolo(4,3-a)quinolin-1-yl)sulfanyl)acetic acid; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013864:Thioglycolates; D014230:Triazoles; D009713:Nucleotidyltransferases; C023226:UDPacetylglucosamine pyrophosphorylase; D014544:Uridine Triphosphate