biostudies-literatureAckloo SStructural Genomics ConsortiumInnovative Medicines InitiativePfizerBayerBristol-Myers Squibb CanadaGenentechJanssen CanadaBoehringer IngelheimMerck KGaATakeda CanadaOntario Genomics InstituteNIGMS NIH HHSNIH HHS1092-1112https://www.ebi.ac.uk/biostudies/studies/S-EPMC11770632biostudies-literatureUnknown68(2)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 evJournal of medicinal chemistryA Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.PMC11770632875510P30 GM124165S10 OD0215271097737OGI-196Cuozzo JWCentrella PAZhang JAhmad STorng WThompson JWatson IHarms NBarsyte-Lovejoy Dvon Rechenberg MBaghaie AJSanthakumar VEdwards AMTaylor RDDong AKramer TRighetto GLKimani SWLento CSchapira MLi FDisch JSGreen SRKeefe ADLoup JHouliston SXu JKwak HAGuilinger JPGibson ELi YSilva MHalabelian LSlakman BLBolotokova AZeng HGhiabi PGuie MAShrestha SHutchinson ALiu JSeitova AWilson DJGilmer JArrowsmith CHAckloo SSzewczyk MLoppnau PUnderkoffler CPerveen SDumas AWolf ERiley PSigel EAMachado RACChau IHerasymenko OKearnes SYadav MBeldar SDehghani-Tafti SGoldman BClark MAKutera MArnautova YASintchak MDFeng JAYazdi AKZhang YWalsh RTBrown PJMulhern CJfalseA Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.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 ev2025-01-01T00:00:00Z2025 Jan2026-06-02T10:09:46.981Z2025-04-03T23:26:46.402ZS-EPMC117706323949509710.1021/acs.jmedchem.4c02010