5FVO

Structure of rat neuronal nitric oxide synthase heme domain in complex with 6-(2-(5-(3-methoxypropylamino)pyridin-3-yl)ethyl)-4- methylpyridin-2-amine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.12 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.

Wang, H.Qin, Y.Li, H.Roman, L.J.Martasek, P.Poulos, T.L.Silverman, R.B.

(2016) J Med Chem 59: 4913

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00273
  • Primary Citation of Related Structures:  
    5FVO, 5FVP, 5FVQ, 5FVR, 5FVS, 5FVT, 5FVU, 5FVV, 5FVW, 5FVX, 5FVY, 5FVZ, 5FW0

  • PubMed Abstract: 

    Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.


  • Organizational Affiliation

    Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NITRIC OXIDE SYNTHASE, BRAIN422Homo sapiensMutation(s): 0 
EC: 1.14.13.39
UniProt
Find proteins for P29476 (Rattus norvegicus)
Explore P29476 
Go to UniProtKB:  P29476
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29476
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.12 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.9α = 90
b = 108.2β = 90
c = 164.29γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-04-20
    Type: Initial release
  • Version 1.1: 2016-06-08
    Changes: Database references
  • Version 1.2: 2024-05-08
    Changes: Data collection, Database references, Derived calculations, Other