Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approach.
Article Details
- CitationCopy to clipboard
Schroder J, Klinger A, Oellien F, Marhofer RJ, Duszenko M, Selzer PM
Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approach.
J Med Chem. 2013 Feb 28;56(4):1478-90. doi: 10.1021/jm3013932. Epub 2013 Feb 12.
- PubMed ID
- 23350811 [ View in PubMed]
- Abstract
In pharmaceutical industry, lead discovery strategies and screening collections have been predominantly tailored to discover compounds that modulate target proteins through noncovalent interactions. Conversely, covalent linkage formation is an important mechanism for a quantity of successful drugs in the market, which are discovered in most cases by hindsight instead of systematical design. In this article, the implementation of a docking-based virtual screening workflow for the retrieval of covalent binders is presented considering human cathepsin K as a test case. By use of the docking conditions that led to the best enrichment of known actives, 44 candidate compounds with unknown activity on cathepsin K were finally selected for experimental evaluation. The most potent inhibitor, 4-(N-phenylanilino)-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile (CP243522), showed a K(i) of 21 nM and was confirmed to have a covalent reversible mechanism of inhibition. The presented approach will have great potential in cases where covalent inhibition is the desired drug discovery strategy.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) N-[(2S)-4-Methyl-1-oxo-1-{[(4S)-3-oxo-1-(2-pyridinylsulfonyl)-4-azepanyl]amino}-2-pentanyl]-1-benzofuran-2-carboxamide Cathepsin K Ki (nM) 0.16 N/A N/A Details N2-[(Benzyloxy)carbonyl]-N-[(3R)-1-{N-[(benzyloxy)carbonyl]-L-leucyl}-4-oxo-3-pyrrolidinyl]-L-leucinamide Cathepsin K Ki (nM) 2.3 N/A N/A Details Tert-Butyl(1s)-1-Cyclohexyl-2-Oxoethylcarbamate Cathepsin K IC 50 (nM) 26 N/A N/A Details