Agonist Lock Touched and Untouched Retinoic Acid Receptor-Related Orphan Receptor-gamma t (ROR gamma t) Inverse Agonists: Classification Based on the Molecular Mechanisms of Action

作者全名："Sun, Nannan; Xie, Qiong; Dang, Yongjun; Wang, Yonghui"

作者地址："[Sun, Nannan; Xie, Qiong; Wang, Yonghui] Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China; [Sun, Nannan; Dang, Yongjun] Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med, Shanghai 200032, Peoples R China; [Sun, Nannan] Fudan Univ, Shanghai 200032, Peoples R China; [Sun, Nannan; Xie, Qiong] Fudan Zhangjiang Inst, Shanghai 201203, Peoples R China; [Sun, Nannan] Zhengzhou Univ, Sch Pharmaceut Sci, Key Lab Adv Drug Preparat Technol, Minist Educ, Zhengzhou 450001, Peoples R China; [Dang, Yongjun] Chongqing Med Univ, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China"

通信作者："Wang, YH (corresponding author), Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China.; Dang, YJ (corresponding author), Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med, Shanghai 200032, Peoples R China.; Dang, YJ (corresponding author), Chongqing Med Univ, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China."

来源：JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000685644300003

JCR分区：Q1

影响因子：7.3

年份：2021

卷号：64

期号：15

开始页：10519

结束页：10536

文献类型：Article

关键词：　

摘要："Retinoic acid receptor-related orphan receptor-gamma-t (ROR gamma t) is a potential drug target for autoimmune diseases with a clear biological mechanism in the Th17/IL-17 pathway. The ""agonist lock"", which is formed by residues His479-Tyr502-Phe506 in ROR gamma t, makes H12 tightly contact H11 in a suitable conformation for coactivator binding and, thus, is related to ROR gamma t transcriptional activation. The inverse agonism of ROR gamma t is complex because not all ROR gamma t inverse agonists directly break the agonist lock to interfere with coactivator recruitment and the transcription of ROR gamma t. Here, we analyze the complex structures, binding modes, and biological activities of various ROR gamma t inverse agonists and classify them as ""agonist lock touched"" and ""agonist lock untouched"" ROR gamma t inverse agonists according to whether they infringe on the agonist lock directly or not. We aim at providing a comprehensive review and insights into drug discovery of ROR gamma t inverse agonists."

基金机构："National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81573276, 81874287, 81973163, 82003577]; Shanghai Biopharmaceutical Science and Technology Supporting Plan [17431902100, 19431900100]; National Science and Technology Major Project [2018ZX09711002-003-014]; Natural Science Foundation of ShanghaiNatural Science Foundation of Shanghai [19ZR1436700]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2019M651383]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (grant nos.: 81573276, 81874287, 81973163, 82003577), the Shanghai Biopharmaceutical Science and Technology Supporting Plan (grant no.: 17431902100, 19431900100), the National Science and Technology Major Project (grant no.: 2018ZX09711002-003-014), the Natural Science Foundation of Shanghai (grant no.: 19ZR1436700) and the China Postdoctoral Science Foundation (no. 2019M651383)."