4MQ6: Pantothenate synthase in complex with 2-(5-methoxy-2-(tosylcarbamoyl)-1H-indol-1-yl)acetic acid

Citation:
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.
PDB ID: 4MQ6Download
MMDB ID: 122692
PDB Deposition Date: 2013/9/15
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4MQ6: dimeric; determined by author
Molecular Components in 4MQ6
Label Count Molecule
Proteins (2 molecules)
2
Pantothenate Synthetase
Molecule annotation
Chemicals (15 molecules)
1
8
2
3
3
4
* Click molecule labels to explore molecular sequence information.

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