Combining pharmacophore models derived from DNA-encoded chemical libraries with structure-based exploration to predict Tankyrase 1 inhibitors.

ABSTRACT: DNA-encoded chemical libraries (DECLs) interrogate the interactions of a target of interest with vast numbers of molecules. DECLs hence provide abundant information about the chemical ligand space for therapeutic targets, and there is considerable interest in methods for exploiting DECL screening data to predict novel ligands. Here we introduce one such approach and demonstrate its feasibility using the cancer-related poly-(ADP-ribose)transferase tankyrase 1 (TNKS1) as a model target. First, DECL affinity selections resulted in structurally diverse TNKS1 inhibitors with high potency including compound 2 with an IC₅₀ value of 0.8 nM. Additionally, TNKS1 hits from four DECLs were translated into pharmacophore models, which were exploited in combination with docking-based screening

SUBMITTER: Montoya AL 

PROVIDER: S-EPMC9805525 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature