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Isoform Selectivity of Adenylyl Cyclase Inhibitors and Identification of Novel Compounds
Author(s) -
Brand Cameron S.,
Hocker Harrison J.,
Gorfe Alemayehu A.,
Cavasotto Claudio N.,
Dessauer Carmen W.
Publication year - 2013
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.27.1_supplement.656.7
Subject(s) - adenylyl cyclase , gene isoform , small molecule , chemistry , in vitro , virtual screening , second messenger system , active site , computational biology , drug discovery , enzyme , biochemistry , gene , biology
Nine membrane‐bound adenylyl cyclase (AC) isoforms produce the 2nd messenger cyclic AMP (cAMP) in response to a wide‐range of stimuli. Reduction of AC activity has well documented benefits, including for heart disease and pain. These roles have inspired development of isoform selective AC inhibitors, a lack of which currently limits exploration and/or treatment of dysfunctions where cAMP plays a role. Known AC inhibitors were flexibly docked to the catalytic site of two AC structure models. Predicted conformations of selective inhibitors suggested flexible catalytic site subregions which confer potency and selectivity. To identify and characterize novel AC inhibitors, a structure‐based virtual screen of 35,000 small drug‐like molecules produced 100 high scoring molecules tested for AC inhibition in vitro. Multiple candidates showed AC inhibition, including isoform selective AC inhibitors. Most known inhibitors are nucleotide analogs; our identified inhibitors show no significant similarity in chemical structure, demonstrating novel selective targeting of the AC catalytic site. Research was funded by Keck Center training fellowship NIGMS T32GM089657 (CSB), and by NIH grants GM60419 and MH060397 (CWD).