Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models provide insight into the agonist-antagonist boundary of the analogues suggesting that the Arg557 residue in the S4-S5 linker might be important for sensing the agonist binding and transmitting signals. These results provide structural insights into the TRPV1 and the protein-ligand interactions at a molecular level.
Bibliographical noteFunding Information:
This work was supported by the Midcareer Researcher Program (NRF-2019R1A2C2006837) funded by the National Research Foundation of Korea (NRF), the Bio & Medical Technology Development Program (NRF-2019M3E5D4065251) and the Medical Research Center (MRC) grant (no. 2018R1A5A2025286) through the National Research Foundation of Korea (NRF). We thank the Korea Institute of Science and Technology Information (KISTI) National Supercomputing Center for providing computing resources (KSC-2019-CRE-0076). This work was also supported in part by the Intramural Program of the Center for Cancer Research, National Cancer Institute, NIH (project Z1A BC 005270).