Isoform Selectivity of Adenylyl Cyclase Inhibitors and Identification of Novel Compounds

BRAND, C.; HOCKER, H.J.; GORFE, A.A.; CAVASOTTO, CLAUDIO N.; DESSAUER, C.W.

Boston, MA

Congreso; Experimental Biology 2013; 2013

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 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.