Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:1.95
Classification:OXIDOREDUCTASE
Release Date:2010-11-03
Deposition Date:2010-06-21
Revision Date:2011-07-13
Molecular Weight:102524.32
Macromolecule Type:Protein
Residue Count:888
Atom Site Count:6619
DOI:10.2210/pdb3nle/pdb
Abstract:
Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((±)-32 and (±)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2''-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.
Resolution:1.95
Classification:OXIDOREDUCTASE
Release Date:2010-11-03
Deposition Date:2010-06-21
Revision Date:2011-07-13
Molecular Weight:102524.32
Macromolecule Type:Protein
Residue Count:888
Atom Site Count:6619
DOI:10.2210/pdb3nle/pdb
Abstract:
Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((±)-32 and (±)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2''-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed.
| Date made available | 2010 |
|---|---|
| Publisher | RCSB-PDB |