1 research outputs found
Discovery of Subtype Selective Janus Kinase (JAK) Inhibitors by Structure-Based Virtual Screening
Janus
kinase inhibitors represent a promising opportunity for the
pharmaceutical intervention of various inflammatory and oncological
indications. Subtype selective inhibition of these enzymes, however,
is still a very challenging goal. In this study, a novel, customized
virtual screening protocol was developed with the intention of providing
an efficient tool for the discovery of subtype selective JAK2 inhibitors.
The screening protocol involves protein ensemble-based docking calculations
combined with an Interaction Fingerprint (IFP) based scoring scheme
for estimating ligand affinities and selectivities, respectively.
The methodology was validated in retrospective studies and was applied
prospectively to screen a large database of commercially available
compounds. Six compounds were identified and confirmed in vitro, with
an indazole-based hit exhibiting promising selectivity for JAK2 vs
JAK1. Having demonstrated that the described methodology is capable
of identifying subtype selective chemical starting points with a favorable
hit rate (11%), we believe that the presented screening concept can
be useful for other kinase targets with challenging selectivity profiles