Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor

Ruo-Lan Wang; Jun Sun; Heng Liu; Shi-Meng Guo; Yu Zhang; Wen Hu; Jiang Wang; Hong Liu; You-Wen Zhuang; Yi Jiang; Xin Xie; H Eric Xu; Yue Wang

doi:10.1038/s41401-025-01606-7

Molecular recognition of two approved drugs Macimorelin and Anamorelin by the growth hormone secretagogue receptor

Acta Pharmacol Sin. 2025 Jun 20. doi: 10.1038/s41401-025-01606-7. Online ahead of print.

Authors

Ruo-Lan Wang^#^{1

2}, Jun Sun^#³, Heng Liu^#¹, Shi-Meng Guo^#¹, Yu Zhang^{1

4}, Wen Hu^{1

5}, Jiang Wang^{1

4}, Hong Liu^{1

2}, You-Wen Zhuang⁶, Yi Jiang⁴, Xin Xie^{7

8

9}, H Eric Xu^{10

11}, Yue Wang¹²

Affiliations

¹ CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
² University of Chinese Academy of Sciences, Beijing, 101408, China.
³ School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
⁴ Lingang Laboratory, Shanghai, 200031, China.
⁵ The Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁶ Medicinal Bioinformatics Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
⁷ CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. xxie@simm.ac.cn.
⁸ University of Chinese Academy of Sciences, Beijing, 101408, China. xxie@simm.ac.cn.
⁹ School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. xxie@simm.ac.cn.
¹⁰ CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. eric.xu@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, 101408, China. eric.xu@simm.ac.cn.
¹² CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. wangyue1@simm.ac.cn.

^# Contributed equally.

PMID: 40542284
DOI: 10.1038/s41401-025-01606-7

Abstract

The growth hormone secretagogue receptor (GHSR) plays a critical role in regulating growth hormone release and metabolic homeostasis. Understanding the molecular mechanisms of ligand-GHSR recognition is essential for developing therapeutic interventions. In this study, we investigated the molecular recognition mechanisms of two clinically approved drugs: Macimorelin (used for diagnosing adult growth hormone deficiency) and Anamorelin (approved in Japan for cancer cachexia). Using high-resolution cryo-electron microscopy, we determined the structures of GHSR bound to Macimorelin and Anamorelin in complex with G_q proteins at resolutions of 2.63 Å and 2.52 Å, respectively. We revealed that both drugs occupied a bifurcated binding pocket divided by a conserved salt bridge between E124^3.33 and R283^6.55. Through systematic mutagenesis and functional studies, we identified the key residues underlying the higher binding affinity of Anamorelin compared to Macimorelin. In addition, structural comparison of GHSR in complex with different G protein subtypes elucidated the mechanisms driving G protein selectivity. Our results provide crucial insights into GHSR-drug interactions and offer valuable guidance for designing more selective and potent GHSR agonists.

Keywords: anamorelin; growth hormone secretagogue receptor; macimorelin; molecular recognition.