Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure-based drug design

Autor:	Fiona H. Marshall, Juan Carlos Mobarec, Susan H. Brown, James C. Errey, Stephen P. Andrews, Jonathan S. Mason, Malcolm Peter Weir, Kelly N. Steele, Ali Jazayeri, Robert M. Cooke, A. O'Brien, Charlotte Fieldhouse, Iryna Teobald, Alastair J. H. Brown, Brown Giles Albert, Bortolato Andrea, John A. Christopher, Asma H. Baig, Chris de Graaf, Stacey M. Southall, Steve P. Watson, Krzysztof Okrasa, Miles Congreve
Rok vydání:	2019
Předmět:	Drug endocrine system media_common.quotation_subject Clinical Biochemistry Allosteric regulation Pharmaceutical Science Computational biology 01 natural sciences Biochemistry Glucagon-Like Peptide-1 Receptor Structure-Activity Relationship Allosteric Regulation Heterocyclic Compounds Drug Discovery Receptors Glucagon Amino Acid Sequence Receptor Molecular Biology media_common Molecular Structure 010405 organic chemistry Chemistry digestive oral and skin physiology Organic Chemistry Antagonist 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Drug Design Molecular Medicine Structure based Glucagon receptor Allosteric Site hormones hormone substitutes and hormone antagonists Protein Binding Signal Transduction
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 29:126611
ISSN:	0960-894X
Popis:	A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C3476.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bd2bdabc56cf80d85af953bc302e66f6 https://doi.org/10.1016/j.bmcl.2019.08.015 Zobrazit plný text záznamu Full Text from ScienceDirect