Structure-based drug discovery of a corticotropin-releasing hormone receptor 1 antagonist using an X-ray free-electron laser

Abstract

Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF1R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF1R complexed with a BMK-I-152 antagonist at 2.75 & ANGS; using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists-BMK-C203 and BMK-C205-and determined the CRF1R/BMK-C203 and CRF1R/BMK-C205 complex structures at 2.6 and 2.2 & ANGS;, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF1R. Structural studies of complexes of a receptor protein for corticotropin-releasing hormone and specific small molecules could guide the development of new antidepressants and drugs for stress-related diseases. The activity of the corticotropin-releasing hormone receptor 1 protein has been associated with many human diseases, including psychiatric disorders, diabetes, cancer, osteoporosis, cardiovascular conditions and neurodegeneration. Hoyoung Kim at Yonsei University in Seoul, South Korea, utilized X-ray free electron laser technology, a method that minimizes sample damage, to determine the protein complexes. Through their study, they unveiled subtle, previously overlooked structural characteristics at two crucial sites. Leveraging these insights, they developed multiple 'antagonist' compounds that disrupt the protein's normal function. One of these antagonists demonstrated significant antidepressant effects in mouse models, sparking hope for potential similar benefits in humans.