Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 8, Pages 1497-1508Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.02.029
Keywords
Indazole; Janus kinase JAK2; Inhibitor; ATP site; Activity; Selectivity; Water network
Funding
- National Research, Development and Innovation Office of Hungary (OTKA) [K 116904]
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Structure based optimization of B39, an indazole-based low micromolar JAK2 virtual screening hit is reported. Analysing the effect of certain modifications on the activity and selectivity of the analogues suggested that these parameters are influenced by water molecules available in the binding site. Simulation of water networks in combination with docking enabled us to identify the key waters and to optimize our primary hit into a low nanomolar JAK2 lead with promising selectivity over JAK1.
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