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Inhibition of soluble guanylyl cyclase by small molecules targeting the catalytic domain
Author(s) -
Vijayaraghavan Jagamya,
Kramp Kristopher,
Harris Michael E.,
Akker Focco
Publication year - 2016
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12427
Subject(s) - soluble guanylyl cyclase , chemistry , guanylate cyclase , nitric oxide , biochemistry , small molecule , in silico , docking (animal) , microbiology and biotechnology , enzyme , biology , medicine , nursing , organic chemistry , gene
Soluble guanylyl cyclase ( sGC ) plays a crucial role in cyclic nucleotide signaling that regulates numerous important physiological processes. To identify new sGC inhibitors that may prevent the formation of the active catalytic domain conformation, we carried out an in silico docking screen targeting a ‘backside pocket’ of the inactive sGC catalytic domain structure. Compounds 1 and 2 were discovered to inhibit sGC even at high/saturating nitric oxide concentrations. Both compounds also inhibit the BAY 58‐2667‐activated sGC as well as BAY 41‐2272‐stimulated sGC activity. Additional biochemical analyses showed that compound 2 also inhibits the isolated catalytic domain, thus demonstrating functional binding to this domain. Both compounds have micromolar affinity for sGC and are potential leads to develop more potent sGC inhibitors.