Interrogating dense ligand chemical space with a forward-synthetic library.
Proc Natl Acad Sci U S A
; 116(23): 11496-11501, 2019 06 04.
Article
en En
| MEDLINE
| ID: mdl-31113876
ABSTRACT
Forward-synthetic databases are an efficient way to enumerate chemical space. We explored here whether these databases are good sources of novel protein ligands and how many molecules are obtainable and in which time frame. Based on docking calculations, series of molecules were selected to gain insights into the ligand structure-activity relationship. To evaluate the novelty of compounds in a challenging way, we chose the ß2-adrenergic receptor, for which a large number of ligands is already known. Finding dissimilar ligands is thus the exception rather than the rule. Here we report on the results, the successful synthesis of 127/240 molecules in just 2 weeks, the discovery of previously unreported dissimilar ligands of the ß2-adrenergic receptor, and the optimization of one series to a K D of 519 nM in only one round. Moreover, the finding that only 3 of 240 molecules had ever been synthesized before indicates that large parts of chemical space are unexplored.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania