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 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.
Bembenek
Scott D
SD
Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States. sbembene@its.jnj.com
Tounge
Brett A
BA
Reynolds
Charles H
CH
D016503:Drug Delivery Systems; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008970:Molecular Weight; D011485:Protein Binding; D054852:Small Molecule Libraries
D008024:Ligands; D054852:Small Molecule Libraries