Selective Discovery of GPCR Ligands within DNA-Encoded Chemical Libraries Derived from Natural Products: A Case Study on Antagonists of Angiotensin II Type I Receptor

Natural products have failed to meet the urgent need for drug discovery in recent decades due to limited resources, necessitating new strategies for re-establishing the key role of natural products in hit screening. This work introduced DNA-encoding techniques into the synthesis of phenolic acid-focused libraries containing 32 000 diverse compounds. Online selection of the library using immobilized angiotensin II type I receptor (AT₁R) resulted in seven phenolic acid derivatives. The half-maximal concentration (IC₅₀) of hit 1 for the right shift of the [¹²⁵I]-Sar1-AngII competition curve was 19.6 nM. Pharmacological examination of renovascular hypertensive rats demonstrated that hit 1 significantly lowered the blood pressure of the animals without changing their heart rates. These results were used to create a general strategy for rapid and unbiased discovery of hits derived from natural products with high throughput and efficiency.