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

Bioorg Med Chem. 2019 Apr 15;27(8):1497-1508. doi: 10.1016/j.bmc.2019.02.029.

Attila Egyed ¹, Dávid Bajusz ¹, György M Keserű ²

Affiliations

1 Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
2 Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary. Electronic address: keseru.gyorgy@ttk.mta.hu.

PMID: 30833158 DOI: 10.1016/j.bmc.2019.02.029

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.

Keywords

ATP site; Activity; Indazole; Inhibitor; Janus kinase JAK2; Selectivity; Water network.

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