A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.

ABSTRACT: Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for ev

SUBMITTER: Ackloo S 

PROVIDER: S-EPMC11770632 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature