205526-38-1Relevant articles and documents
Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure ?
Martin, Charlotte,Gimenez, Luis E.,Williams, Savannah Y.,Jing, Yu,Wu, Yiran,Hollanders, Charlie,Van Der Poorten, Olivier,Gonzalez, Simon,Van Holsbeeck, Kevin,Previti, Santo,Lamouroux, Arthur,Zhao, Suwen,Tourwé, Dirk,Stevens, Raymond C.,Cone, Roger D.,Ballet, Steven
supporting information, p. 357 - 369 (2020/12/01)
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.
Drug Design Inspired by Nature: Crystallographic Detection of an Auto-Tailored Protease Inhibitor Template
Gall, Flavio M.,Hohl, Deborah,Frasson, David,Wermelinger, Tobias,Mittl, Peer R. E.,Sievers, Martin,Riedl, Rainer
, p. 4051 - 4055 (2019/02/16)
De novo drug discovery is still a challenge in the search for potent and selective modulators of therapeutically relevant target proteins. Here, we disclose the unexpected discovery of a peptidic ligand 1 by X-ray crystallography, which was auto-tailored by the therapeutic target MMP-13 through partial self-degradation and subsequent structure-based optimization to a highly potent and selective β-sheet peptidomimetic inhibitor derived from the endogenous tissue inhibitors of metalloproteinases (TIMPs). The incorporation of non-proteinogenic amino acids in combination with a cyclization strategy proved to be key for the de novo design of TIMP peptidomimetics. The optimized cyclic peptide 4 (ZHAWOC7726) is membrane permeable with an IC50 of 21 nm for MMP-13 and an attractive selectivity profile with respect to a polypharmacology approach including the anticancer targets MMP-2 (IC50: 170 nm) and MMP-9 (IC50: 140 nm).
Ligands for opioid receptors
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, (2008/06/13)
The present invention provides compounds, and pharmaceutical preparations thereof, that bind selectively to mammalian opioid receptors. The present set of compounds comprises full agonists, partial agonists, and antagonists of mammalian opioid receptors.
