Conformation-dependent ligand hot spots in the spliceosomal RNA helicase BRR2.

ABSTRACT: The conversion of hits to leads in drug discovery involves the elaboration of chemical core structures to increase their potency. In fragment-based drug discovery, low-molecular-weight compounds are tested for protein binding and are subsequently modified, with the tacit assumption that the binding mode of the original hit will be conserved among the derivatives. However, deviations from binding mode conservation are rather frequently observed, but potential causes of these alterations remain incompletely understood. Here, two crystal forms of the spliceosomal RNA helicase BRR2 were employed as a test case to explore the consequences of conformational changes in the target protein on the binding behaviour of fragment derivatives. The initial fragment, sulfaguanidine, bound at the interface

SUBMITTER: Vester K 

PROVIDER: S-EPMC10071561 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature