2 research outputs found
Research News. Publications, 2017. Volume 1
Publications that appeared during the period January 1 through June 30, 201
Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor
Adenylyl
cyclase 2 (AC2) is one of nine membrane-bound isoforms
of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important
second messenger molecule. Upregulation of AC2 is linked to cancers
like pancreatic and small intestinal neuroendocrine tumors (NETs).
The structures of the various isoforms of adenylyl cyclases are highly
homologous, posing a significant challenge to drug discovery efforts
for an effective, isoform-selective modulator of AC2. In a previous
study, a screen identified a potential isoform-selective and noncompetitive
inhibitor of AC2, SKF83566. In the present study, molecular modeling
is used to explore the mode of inhibition of AC2 by SKF83566 and to
investigate the active enantiomer of SKF83566. Homology models of
hAC2 were built based on canine AC5-C1a and rat AC2-C2a templates.
With these models, a combination of flexible docking, molecular dynamics
simulations, and free energy calculations using the MM/GBSA methodology
suggested an allosteric mechanism in which (<i>S</i>)-SKF83566
binds to an allosteric site near ATP and alters the protein conformation
of the ATP binding site, potentially preventing the adenosine moiety
of ATP from forming an archlike shape to form cAMP. The predicted
binding preference for the (<i>S</i>)-SKF83566 enantiomer
and the predicted free energy are consistent with the experimental
data