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Structure‐Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity
Author(s) -
Nordqvist Anneli,
O'Mahony Gavin,
FridénSaxin Maria,
Fredenwall Marlene,
Hogner Anders,
Granberg Kenneth L.,
Aagaard Anna,
Bäckström Stefan,
Gunnarsson Anders,
Kaminski Tim,
Xue Yafeng,
Dellsén Anita,
Hansson Eva,
Hansson Pia,
Ivarsson Ida,
Karlsson Ulla,
Bamberg Krister,
Hermansson Majlis,
Georgsson Jennie,
Lindmark Bo,
Edman Karl
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600529
Subject(s) - mineralocorticoid receptor , pharmacology , chemistry , drug , receptor , selectivity , mineralocorticoid , medicine , biochemistry , catalysis
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 p K 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 p K i =7.3. Two protein–ligand X‐ray structures were determined, confirming the hypothesized binding mode for the designed compounds.