<i>N</i>MR²-Based Drug Discovery Pipeline Presented on the Oncogenic Protein KRAS.

ABSTRACT: Fragment-based drug discovery has emerged as a powerful approach for developing therapeutics against challenging targets, including the GTPase KRAS. Here, we report an NMR-based screening campaign employing state-of-the-art techniques to evaluate a library of 890 fragments against the oncogenic KRAS G12V mutant bound to GMP-PNP. Further HSQC titration experiments identified hits with low millimolar affinities binding within the SI/SII switch region, which forms the binding interface for the effector proteins. To elucidate the binding modes, we applied NMR molecular replacement (NMR²) structure calculations, bypassing the need for a conventional protein resonance assignment. Traditionally, NMR² relies on isotope-filtered nuclear Overhauser effect spectros

SUBMITTER: Butikofer M 

PROVIDER: S-EPMC12022975 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature