Watanabe Masaki, Nakamura-Nakayama Mariko, Fujihara Michiko, Kawasaki Mayu, Nakano Shogo, Kakuta Hiroki
Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
AIBIOS K.K., Tri-Seven Roppongi 8F, 7-7-7 Roppongi, Minato-ku, Tokyo 106-0032, Japan.
ACS Med Chem Lett. 2022 Jan 21;13(2):211-217. doi: 10.1021/acsmedchemlett.1c00575. eCollection 2022 Feb 10.
Screening for small-molecule modulators targeting a particular receptor is frequently based on measurement of , i.e., the binding constant between the receptor and the compound of interest. However, values also reflect binding at receptor protein sites other than the modulatory site. We designed derivatives of retinoid X receptor (RXR) antagonist CBTF-EE () with modifications that altered their conformational flexibility. Compounds , and , showed quite similar values, but , exhibited 10-fold higher values than those of ,. Further, , showed potent RXR-antagonistic activity, while , were inactive. These results suggest that increased conformational flexibility promotes binding at nontarget receptor sites. In this situation, conventional determination of is less effective for screening purposes than the determination of using a ligand that binds specifically to the site regulating transcriptional activity. Thus, the use of values for orthosteric ligands may increase the hit rate in screening active regulatory molecules.
针对特定受体筛选小分子调节剂通常基于对 的测量，即受体与目标化合物之间的结合常数。然而， 值也反映了在调节位点以外的受体蛋白位点的结合情况。我们设计了视黄酸X受体（RXR）拮抗剂CBTF - EE（）的衍生物，通过修饰改变其构象灵活性。化合物 、 和 显示出相当相似的 值，但 表现出比 、 高10倍的 值。此外， 显示出有效的RXR拮抗活性，而 无活性。这些结果表明，增加的构象灵活性促进了在非靶标受体位点的结合。在这种情况下，传统的 测定对于筛选目的而言不如使用特异性结合调节转录活性位点的配体来测定 有效。因此，使用正构配体的 值可能会提高筛选活性调节分子时的命中率。
