期刊
CHEMMEDCHEM
卷 11, 期 1, 页码 38-42出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500414
关键词
drug design; fragment-based screening; group efficiency; Mycobacterium tuberculosis; pantothenate synthetase
资金
- Bill & Melinda Gates Foundation
- UK Biotechnology and Biological Sciences Research Council [BB/D006104/1]
- Fundacao para a Ciencia e Tecnologia (FCT), Portugal
- Homerton College, Cambridge
- Agency for Science, Technology and Research (A*STAR), Singapore
- BBSRC [BB/D006104/1] Funding Source: UKRI
- EPSRC [EP/K039520/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D006104/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/K039520/1] Funding Source: researchfish
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.
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