Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity

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• 作者：Dr. Anneli Nordqvist ; Dr. Gavin O'Mahony ; Dr. Maria Fridé ; n-Saxin ; Marlene Fredenwall ; Dr. Anders Hogner ; Dr. Kenneth L. Granberg ; Dr. Anna Aagaard ; Dr. Stefan Bä ; ckströ ; m ; Dr. Anders Gunnarsson ; Dr. Tim Kaminski ; Dr. Yafeng Xue ; Anita Dellsé ; n ; Eva Hansson ; Pia Hansson ; Ida Ivarsson ; Ulla Karlsson ; Dr. Krister Bamberg ; Majlis Hermansson ; Dr. Jennie Georgsson ; Bo Lindmark and Dr. Karl Edman
• 刊名：ChemMedChem
• 出版年：2017
• 出版时间：January 5, 2017
• 年：2017
• 卷：12
• 期：1
• 页码：50-65
• 全文大小：1774K
• ISSN：1860-7187

文摘

The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in the regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of nonsteroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign. The compound bound to MR with pK_i=6.6, but displayed poor selectivity over the glucocorticoid receptor (GR) and the progesterone receptor (PR). Following X-ray crystallography of MR in complex with the HTS hit, a compound library was designed that explored an induced-fit hypothesis that required movement of the Met852 side chain. An improvement in MR selectivity of 11- to 79-fold over PR and 23- to 234-fold over GR was obtained. Given the U-shaped binding conformation, macrocyclizations were explored, yielding a macrocycle that bound to MR with pK_i=7.3. Two protein–ligand X-ray structures were determined, confirming the hypothesized binding mode for the designed compounds.