A conformational transition in the adenylyl cyclase catalytic site yields different binding modes for ribosyl-modified and unmodified nucleotide inhibitors.
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.
Wang
Jenna L
JL
Molecular Graphics and Modeling Laboratory, University of Kansas, Lawrence, KS 66045, USA.
Guo
Jian-Xin
JX
Zhang
Qi-Yuan
QY
Wu
Jay J-Q
JJ
Seifert
Roland
R
Lushington
Gerald H
GH
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000737:chemistry*; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D007202:Indicators and Reagents; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009711:Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D012266:Ribose
D000067956:Adenylyl Cyclase Inhibitors; D007202:Indicators and Reagents; D008024:Ligands; D009711:Nucleotides; D010710:Phosphates; D011687:Purines; D011743:Pyrimidines; D012266:Ribose; D000262:Adenylyl Cyclases