Discovery of ICOS-targeted small molecules using pharmacophore-based screening

This study represents the development and validation of a virtual screening strategy to identify small molecules that bind a novel druggable binding pocket in human ICOS. We used a lipophilic canyon in the apo-structure of ICOS and the ICOS/ICOS-L interface individually as templates for molecular dynamics simulation to generate 3D pharmacophores subsequently used for virtual screening campaigns. Our strategy was successful finding a first-in-class small molecule ICOS binder (5P, KD value = 108.08 ± 26.76 µM) and validating biophysical screening platforms for ICOS-targeted small molecules. We anticipate that future structural optimization of 5P will result in the discovery of high affinity chemical ligands for ICOS.PMID:37845178 | DOI:10.1002/cmdc.202300305

Source: ChemMedChem - October 16, 2023 Category: Chemistry Authors: Laura Calvo-Barreiro Valerij Talagayev Szymon Pach Somaya A Abdel-Rahman Gerhard Wolber Moustafa Gabr Source Type: research