4MQ6

Pantothenate synthase in complex with 2-(5-methoxy-2-(tosylcarbamoyl)-1H-indol-1-yl)acetic acid

Summary for 4MQ6

• Entry DOI: 10.2210/pdb4mq6/pdb
• Descriptor: Pantothenate synthetase, ETHANOL, (5-methoxy-2-{[(4-methylphenyl)sulfonyl]carbamoyl}-1H-indol-1-yl)acetic acid, ... (5 entities in total)
• Functional Keywords: alpha beta 3-layer(aba) sandwich rossmann fold, pantoate-ligase, atp binding, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 67042.76

Authors

Silvestre, H.L.,Blundell, T.L. (deposition date: 2013-09-15, release date: 2014-08-27, Last modification date: 2024-02-28)

Primary citation

Hung, A.W.,Silvestre, H.L.,Wen, S.,George, G.P.,Boland, J.,Blundell, T.L.,Ciulli, A.,Abell, C.
Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis.
Chemmedchem, 11:38-42, 2016

PubMed 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.

PubMed: 26486566
DOI: 10.1002/cmdc.201500414

Experimental method

X-RAY DIFFRACTION (1.7 Å)