Ligand efficiency and fragment-based drug discovery

The use of fragment-based drug discovery (FBDD) has increased in recent years since it is more likely to produce a better optimized compound of lower molecular weight. Ligand efficiency (LE) has become important for assessing fragments, HTS hits, and resulting optimized ligands. LE is useful for com...

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Published inDrug discovery today Vol. 14; no. 5; pp. 278 - 283
Main Authors Bembenek, Scott D., Tounge, Brett A., Reynolds, Charles H.
Format Journal Article
LanguageEnglish
Published Kidlington Elsevier Ltd 01.03.2009
Elsevier
Subjects
Biological and medical sciences
Drug Delivery Systems
Drug Discovery
General pharmacology
Humans
Ligands
Medical sciences
Molecular Weight
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Protein Binding
Small Molecule Libraries
Drug
Pharmaceutical technology
Efficiency
Ligand
Research and development
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Summary:The use of fragment-based drug discovery (FBDD) has increased in recent years since it is more likely to produce a better optimized compound of lower molecular weight. Ligand efficiency (LE) has become important for assessing fragments, HTS hits, and resulting optimized ligands. LE is useful for comparing ligands of equal molecular weight, but is ineffective for comparisons of ligands of differing molecular weight. LE has a strong dependence on molecular size, which has led us to develop a size-independent efficiency score termed fit quality. Evaluating FBDD examples from the literature using LE and fit quality, we find that, in general, the LEs of starting fragments are greater than those of larger, more elaborated, structures. Fit quality scores, however, tend to improve upon optimization of the fragments.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
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ObjectType-Review-1
ISSN:1359-6446
1878-5832
DOI:10.1016/j.drudis.2008.11.007