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Pose, duplicate, then elaborate: Steps towards increased affinity for inhibitors targeting the specificity surface of the Pim-1 kinase
Ist Teil von
European journal of medicinal chemistry, 2023-01, Vol.245, p.114914-114914, Article 114914
Ort / Verlag
Elsevier Masson SAS
Erscheinungsjahr
2023
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
In this study, fragment-sized hits binding to Pim-1 kinase with initially modest affinity were further optimized by combining computational, synthetic and crystallographic expertise, eventually resulting in potent ligands with affinities in the nanomolar range that address rarely-targeted regions of Pim-1 kinase. Starting from a set of crystallographically validated, chemically distinct fragments that bind to Pim-1 kinase but lack typical nucleotide mimetic structures, a library of extended fragments was built by exhaustive in silico reactions. After docking, minimization, clustering, visual inspection of the top-ranked compounds, and evaluation of ease of synthetic accessibility, either the original compound or a close derivative was synthesized and tested against Pim-1. For compounds showing the highest degree of Pim-1 inhibition the binding mode was determined crystallographically. Following a structure-guided approach, these were further optimized in a subsequent design cycle improving the compound's initial affinity by several orders of magnitude while synthesizing only a comparatively modest number of derivatives. The combination of computational and experimental approaches resulted in the development of a reasonably potent, novel molecular scaffold for inhibition of Pim-1 that targets specific surface regions, such as the interaction with R122 and P123 of the hinge region, which has been less frequently investigated in similar studies.
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•Fragment-based drug design of PIM-1-inhibitors.•Design strategy combines computational, synthetic and crystallographic methods.•Structure-guided optimization resulted in potent PIM-1 inhibitors.•6-amino-indolin-2-one based PIM-1 kinase inhibitors.