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Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure†
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-14 , DOI: 10.1021/acs.jmedchem.0c01620 Charlotte Martin 1 , Luis E Gimenez 2 , Savannah Y Williams 2 , Yu Jing 3 , Yiran Wu 3 , Charlie Hollanders 1 , Olivier Van der Poorten 1 , Simon Gonzalez 1 , Kevin Van Holsbeeck 1 , Santo Previti 1 , Arthur Lamouroux 1 , Suwen Zhao 3, 4 , Dirk Tourwé 1 , Raymond C Stevens 3, 4 , Roger D Cone 2, 5 , Steven Ballet 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-11-14 , DOI: 10.1021/acs.jmedchem.0c01620 Charlotte Martin 1 , Luis E Gimenez 2 , Savannah Y Williams 2 , Yu Jing 3 , Yiran Wu 3 , Charlie Hollanders 1 , Olivier Van der Poorten 1 , Simon Gonzalez 1 , Kevin Van Holsbeeck 1 , Santo Previti 1 , Arthur Lamouroux 1 , Suwen Zhao 3, 4 , Dirk Tourwé 1 , Raymond C Stevens 3, 4 , Roger D Cone 2, 5 , Steven Ballet 1
Affiliation
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The melanocortin receptors (MC1R–MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist SHU-9119 (Ac-Nle4-c[Asp5-His6-DNal(2′)7-Arg8-Trp9-Lys10]-NH2). These analogues were pharmacologically characterized in vitro, giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle4, DNal(2′)7, and Trp9 residues in SHU-9119, as well as the amide linkage between the Asp5 and Lys10 side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.
中文翻译：
基于 SHU-9119-hMC4R 共晶结构的黑皮质素 4 受体配体结构设计†
黑皮质素受体 (MC1R-MC5R) 属于 A 类 G 蛋白偶联受体 (GPCR)，已知在正常和疾病状态下具有受体特异性作用。MC4R 的选择性特别令人感兴趣，因为它涉及各种代谢紊乱，包括肥胖、喂养调节和性功能障碍。为了进一步提高 MC4R（抗）激动剂肽配体的效力和选择性，我们基于 MC4R 最近的晶体结构与充分表征的拮抗剂SHU-9119 (Ac-Nle 4 - c[Asp 5 -His 6 -DNal(2′) 7 -Arg 8 -Trp 9 -Lys 10 ]-NH2 )。这些类似物在体外进行了药理学表征，为利用结合位点亚袋递送更具选择性的配体提供了关键见解。更具体地说，发现SHU-9119中 Nle 4、DNal(2') 7和 Trp 9残基的侧链，以及 Asp 5和 Lys 10侧链之间的酰胺键，代表了结构特征。 hMC4R/hMC3R 选择开关。
更新日期：2021-01-14
中文翻译：
基于 SHU-9119-hMC4R 共晶结构的黑皮质素 4 受体配体结构设计†
黑皮质素受体 (MC1R-MC5R) 属于 A 类 G 蛋白偶联受体 (GPCR)，已知在正常和疾病状态下具有受体特异性作用。MC4R 的选择性特别令人感兴趣，因为它涉及各种代谢紊乱，包括肥胖、喂养调节和性功能障碍。为了进一步提高 MC4R（抗）激动剂肽配体的效力和选择性，我们基于 MC4R 最近的晶体结构与充分表征的拮抗剂SHU-9119 (Ac-Nle 4 - c[Asp 5 -His 6 -DNal(2′) 7 -Arg 8 -Trp 9 -Lys 10 ]-NH2 )。这些类似物在体外进行了药理学表征，为利用结合位点亚袋递送更具选择性的配体提供了关键见解。更具体地说，发现SHU-9119中 Nle 4、DNal(2') 7和 Trp 9残基的侧链，以及 Asp 5和 Lys 10侧链之间的酰胺键，代表了结构特征。 hMC4R/hMC3R 选择开关。
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