Computationally Guided Identification of Novel Mycobacterium tuberculosis GlmU Inhibitory Leads, Their Optimization, and in Vitro Validation

ACS Combinatorial Science
Rukmankesh MehraAmit Nargotra

Abstract

Mycobacterium tuberculosis (Mtb) infections are causing serious health concerns worldwide. Antituberculosis drug resistance threatens the current therapies and causes further need to develop effective antituberculosis therapy. GlmU represents an interesting target for developing novel Mtb drug candidates. It is a bifunctional acetyltransferase/uridyltransferase enzyme that catalyzes the biosynthesis of UDP-N-acetyl-glucosamine (UDP-GlcNAc) from glucosamine-1-phosphate (GlcN-1-P). UDP-GlcNAc is a substrate for the biosynthesis of lipopolysaccharide and peptidoglycan that are constituents of the bacterial cell wall. In the current study, structure and ligand based computational models were developed and rationally applied to screen a drug-like compound repository of 20,000 compounds procured from ChemBridge DIVERSet database for the identification of probable inhibitors of Mtb GlmU. The in vitro evaluation of the in silico identified inhibitor candidates resulted in the identification of 15 inhibitory leads of this target. Literature search of these leads through SciFinder and their similarity analysis with the PubChem training data set (AID 1376) revealed the structural novelty of these hits with respect to Mtb GlmU. IC50 of the...Continue Reading

References

Jun 6, 2000·Journal of Biomolecular Screening·J H ZhangK R Oldenburg
Feb 23, 2002·Journal of Molecular Graphics & Modelling·Alexander Golbraikh, Alexander Tropsha
Sep 6, 2002·Journal of Medicinal Chemistry·Yvonne C MartinLinda M Traphagen
Mar 27, 2003·Molecular Microbiology·Christopher M SassettiEric J Rubin
Jan 27, 2004·Journal of Chemical Information and Computer Sciences·Nicolas BaurinLuc Morin-Allory
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
Apr 28, 2006·Antimicrobial Agents and Chemotherapy·Euan BurtonSrinivasa Madhyastha
Nov 30, 2006·Drug Discovery Today·Peter Willett
Feb 10, 2007·Journal of Chemical Information and Modeling·Jean-François Truchon, Christopher I Bayly
May 3, 2007·Protein Science : a Publication of the Protein Society·Laurence R OlsenSteven L Roderick
Nov 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Stéphane BetziYves Collette
Feb 13, 2008·FEMS Microbiology Reviews·Hélène BarreteauDidier Blanot
Mar 11, 2008·Current Opinion in Chemical Biology·Joe Zhongxiang Zhou
Nov 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Rommie E AmaroJ Andrew McCammon
Dec 17, 2008·Antimicrobial Agents and Chemotherapy·Jossy van den BoogaardRob E Aarnoutse
Feb 25, 2009·Acta Crystallographica. Section D, Biological Crystallography·Zhening ZhangChristopher J Squire
Apr 8, 2009·Antimicrobial Agents and Chemotherapy·Mark P PereiraEric D Brown
May 2, 2009·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Sunil Kumar VermaBalaji Prakash
Oct 17, 2009·Journal of Medicinal Chemistry·Andrew R LeachRobin Taylor
Apr 9, 2010·Journal of Chemical Information and Modeling·K Shawn WattsJohn C Shelley
May 20, 2011·Archives of Microbiology·Yan ZhouYufang Ma
Jul 8, 2011·BMC Pharmacology·Deepak SinglaGajendra P S Raghava
Oct 11, 2011·The Journal of Biological Chemistry·Ed T BuurmanAdam B Shapiro
Oct 25, 2011·PLoS Computational Biology·Shun-Chieh YangCalvin Yu-Chian Chen
Dec 6, 2011·Nucleic Acids Research·Yanli WangStephen H Bryant
May 16, 2013·Journal of Chemical Information and Modeling·Sarah R LangdonJulian Blagg
Sep 10, 2013·Bioorganic & Medicinal Chemistry Letters·David L LinMarcelo E Tolmasky
Sep 26, 2013·PloS One·Vasanthanathan Poongavanam, Jacob Kongsted
Oct 26, 2013·Organic & Biomolecular Chemistry·Anh Thu TranRichard J Payne
Mar 7, 2014·Journal of Chemical Information and Modeling·Shagun KrishnaDibyendu Banerjee

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Citations

Apr 5, 2017·ACS Combinatorial Science·M G Finn
Jul 31, 2019·Journal of Biomolecular Structure & Dynamics·Muhammad Tahir Khan, Shaukat Iqbal Malik
Nov 25, 2018·Scientific Reports·Rukmankesh MehraKasper P Kepp
Nov 28, 2018·Expert Opinion on Drug Discovery·Alexey Aleksandrov, Hannu Myllykallio
Oct 31, 2020·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Sajid AliMuhammad Irfan
Jul 21, 2017·Journal of Chemical Information and Modeling·Priya MahajanAmit Nargotra

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