caa a22 4500 605511470 CHVBK 20210128100651.0 cr unu---uuuuu 210128e20150701xx s 000 0 eng 10.1007/s00894-015-2704-3 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2704-3 Structure-based design of diverse inhibitors of Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase: combined molecular docking, dynamic simulation, and biological activity [Elektronische Daten] [Vijay Soni, Priyanka Suryadevara, Dharmarajan Sriram, Santhosh Kumar, Vinay Nandicoori, Perumal Yogeeswari] 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 (GlmUMtb), 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 glmUMtb. 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 10ns 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. Graphical Abstract Superimposed structures of glmuMtb - compound 4 complex collected at various intervals during molecular dynamics simulations displaying the stability of the complex Springer-Verlag Berlin Heidelberg, 2015 Isothermal titration calorimetry (ITC) nationallicence Lipophilic cell wall nationallicence Molecular dynamics (MD) simulations nationallicence N-acetylglucosamine-1-phosphate uridyltransferase (GlmUMtb) nationallicence Soni Vijay Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut Suryadevara Priyanka Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut Sriram Dharmarajan Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut Kumar Santhosh CSIR-Institute of Genomics and Integrative Biology, Mathura Road, 110020, New Delhi, India aut Nandicoori Vinay National Institute of Immunology, Aruna Asaf Ali Marg, 110067, New Delhi, India aut Yogeeswari Perumal Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/7(2015-07-01), 1-12 1610-2940 21:7<1 2015 21 894 https://doi.org/10.1007/s00894-015-2704-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2704-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Soni Vijay Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut NATIONALLICENCE 700 1- Suryadevara Priyanka Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut NATIONALLICENCE 700 1- Sriram Dharmarajan Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut NATIONALLICENCE 700 1- Kumar Santhosh CSIR-Institute of Genomics and Integrative Biology, Mathura Road, 110020, New Delhi, India aut NATIONALLICENCE 700 1- Nandicoori Vinay National Institute of Immunology, Aruna Asaf Ali Marg, 110067, New Delhi, India aut NATIONALLICENCE 700 1- Yogeeswari Perumal Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad campus, Shameerpet, Jawahar Nagar, R.R. District, India aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/7(2015-07-01), 1-12 1610-2940 21:7<1 2015 21 894