A conformational transition in the adenylyl cyclase catalytic site yields different binding modes for ribosyl-modified
and unmodified nucleotide inhibitors

Abstract

Abstract—Adenylyl cyclases (ACs) are promising pharmacological targets for treating heart failure, cancer, and psychosis. Ribosesubstituted nucleotides have been reported as a potent family of AC inhibitors. In silico analysis of the docked conformers of such
nucleotides in AC permits assembly of a consistent, intuitive QSAR model with strong correlation relative to measured pKi values. Energy decomposition suggests that the MANT group effects an AC conformational transition upon ligand binding.