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The impact of binding site waters on the activity/selectivity trade-off of Janus kinase 2 (JAK2) inhibitors.

The impact of binding site waters on the activity/selectivity trade-off of Janus kinase 2 (JAK2) inhibitors.

Authors :
Egyed, Attila
Bajusz, Dávid
Keserű, György M.
Source :
Bioorganic & Medicinal Chemistry. Apr2019, Vol. 27 Issue 8, p1497-1508. 12p.
Publication Year :
2019

Abstract

Graphical abstract Abstract 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
09680896
Volume :
27
Issue :
8
Database :
Academic Search Index
Journal :
Bioorganic & Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
135492566
Full Text :
https://doi.org/10.1016/j.bmc.2019.02.029