New Frontiers in Druggability
- 11 August 2015
- journal article
- perspective
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 58 (23), 9063-9088
- https://doi.org/10.1021/acs.jmedchem.5b00586
Abstract
A powerful early approach to evaluating the druggability of proteins involved determining the hit rate in NMR-based screening of a library of small compounds. Here, we show that a computational analog of this method, based on mapping proteins using small molecules as probes, can reliably reproduce druggability results from NMR-based screening and can provide a more meaningful assessment in cases where the two approaches disagree. We apply the method to a large set of proteins. The results show that, because the method is based on the biophysics of binding rather than on empirical parametrization, meaningful information can be gained about classes of proteins and classes of compounds beyond those resembling validated targets and conventionally druglike ligands. In particular, the method identifies targets that, while not druggable by druglike compounds, may become druggable using compound classes such as macrocycles or other large molecules beyond the rule-of-five limit.Keywords
Funding Information
- National Institute of General Medical Sciences (GM064700, GM094551)
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