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A druggable binding site in the emerging diuretic target ROMK (893.15)
Author(s) -
Swale Daniel,
Sheehan Jonathan,
Meiler Jens,
Denton Jerod
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.893.15
Subject(s) - druggability , chemistry , in silico , docking (animal) , potassium channel , inward rectifier potassium ion channel , pharmacology , computational biology , biophysics , biochemistry , biology , ion channel , medicine , receptor , gene , nursing
An emerging body of evidence suggests the Renal Outer Medullary potassium channel (ROMK, Kir1.1) represents a novel diuretic target for the treatment of hypertension. We recently employed high‐throughput screening and medicinal chemistry to develop the first highly selective small‐molecule ROMK inhibitor, VU591 (Bhave et al., 2011). Its clean ancillary pharmacology raises important questions about how drug selectivity can be achieved in a structurally simple K+ channel. The voltage‐dependence of VU591 block suggests the binding site is located in the membrane‐spanning pore, prompting us to perform scanning mutagenesis analysis of this region of ROMK. Most mutations had no effect on VU591 sensitivity; however, mutation of Val168 and Asp171, which are unique to ROMK among other inward rectifier K+ channels, led to side chain‐specific changes in channel block. In support of our functional data, comparative molecular modeling and in silico docking analysis revealed an energetically favorable interaction between VU591 and the side chains of V168 and N171. This study reveals key structural elements required for selective inhibition of this emerging diuretic target. Grant Funding Source : Supported by NIH 1RO1DK082884 to Jerod S Denton