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

  • Bioorg Med Chem. 2007 Apr 15;15(8):2993-3002. doi: 10.1016/j.bmc.2007.02.014.
Jenna L Wang  1 ,  Jian-Xin Guo ,  Qi-Yuan Zhang ,  Jay J-Q Wu ,  Roland Seifert ,  Gerald H Lushington
Affiliations
  • 1. Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, KS 66045, USA.
PMID: 17329110 DOI: 10.1016/j.bmc.2007.02.014
Abstract

Adenylyl cyclases (ACs) are promising pharmacological targets for treating heart failure, Cancer, and psychosis. Ribose-substituted 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 pK(i) values. Energy decomposition suggests that the MANT group effects an AC conformational transition upon ligand binding.

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