title: Computationally Guided Identification of Novel Mycobacterium tuberculosis GlmU Inhibitory Leads, Their Optimization, and in Vitro Validation.
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 most potent identified inhibitory lead (5810599) was found to be 9.018 ± 0.04 μM. Molecular dynamics (MD) simulation of this inhibitory lead (5810599) in complex with protein affirms the stability of the lead within the binding pocket and also emphasizes on the key interactive residues for further designing. Binding site analysis of the acetyltransferase pocket with respect to the identified structural moieties provides a thorough analysis for carrying out the lead optimization studies.
authors.affiliation: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.
authors.forename: Rukmankesh
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Clinical Microbiology, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.
authors.forename: Chitra
authors.initials: C
authors.lastname: Rani
authors.affiliation: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.
authors.forename: Priya
authors.initials: P
authors.lastname: Mahajan
authors.affiliation: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.
authors.forename: Ram Ashrey
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Clinical Microbiology, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.
authors.forename: Inshad Ali
authors.initials: IA
authors.lastname: Khan
authors.affiliation: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.|Academy of Scientific and Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu 180001, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Nargotra
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D055808:Drug Discovery; D015964:Gene Expression Regulation, Bacterial; D057166:High-Throughput Screening Assays; D008024:Ligands; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; C532100:GlmU protein, Mycobacterium tuberculosis; D008024:Ligands; D009097:Multienzyme Complexes
keywords: GlmU inhibitors; Mycobacterium tuberculosis; QSAR; acetyltransferase inhibitors; computational screening; in silico