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Title: Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis
Authors: Hung, A.W 
Silvestre, H.L
Wen, S
George, G.P.C
Boland, J
Blundell, T.L
Ciulli, A
Abell, C
Keywords: antimycobacterial agent
bacterial enzyme
enzyme inhibitor
functional group
pantothenate synthetase
pantothenate synthetase inhibitor
unclassified drug
enzyme inhibitor
pantothenate synthetase
peptide synthase
tuberculostatic agent
binding affinity
crystal structure
drug binding site
drug design
drug potency
drug protein binding
drug screening
drug structure
fragment based screening
group efficiency analysis
isothermal titration calorimetry
ligand binding
Mycobacterium tuberculosis
priority journal
substitution reaction
X ray crystallography
antagonists and inhibitors
chemical structure
dose response
drug development
molecular model
Mycobacterium tuberculosis
structure activity relation
Antitubercular Agents
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Discovery
Enzyme Inhibitors
Models, Molecular
Molecular Structure
Mycobacterium tuberculosis
Peptide Synthases
Structure-Activity Relationship
Issue Date: 2016
Citation: Hung, A.W, Silvestre, H.L, Wen, S, George, G.P.C, Boland, J, Blundell, T.L, Ciulli, A, Abell, C (2016). Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis. ChemMedChem 11 (1) : 38-42. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine-tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment-based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Source Title: ChemMedChem
ISSN: 18607179
DOI: 10.1002/cmdc.201500414
Rights: Attribution 4.0 International
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