5VUZ

Structure of human neuronal nitric oxide synthase heme domain in complex with 7-(((3-(Pyridin-3-yl)propyl)amino)methyl)quinolin-2-amine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.

Pensa, A.V.Cinelli, M.A.Li, H.Chreifi, G.Mukherjee, P.Roman, L.J.Martasek, P.Poulos, T.L.Silverman, R.B.

(2017) J Med Chem 60: 7146-7165

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00835
  • Primary Citation of Related Structures:  
    5VUI, 5VUJ, 5VUK, 5VUL, 5VUM, 5VUN, 5VUO, 5VUP, 5VUQ, 5VUR, 5VUS, 5VUT, 5VUU, 5VUV, 5VUW, 5VUX, 5VUY, 5VUZ, 5VV0, 5VV1, 5VV2, 5VV3, 5VV4, 5VV5, 5VV6, 5VV7, 5VV8, 5VV9, 5VVA, 5VVB, 5VVC, 5VVD, 5VVG, 5VVN

  • PubMed Abstract: 

    Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.


  • Organizational Affiliation

    Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Northwestern University , 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, brain
A, B
421Homo sapiensMutation(s): 2 
Gene Names: NOS1
EC: 1.14.13.39
UniProt & NIH Common Fund Data Resources
Find proteins for P29475 (Homo sapiens)
Explore P29475 
Go to UniProtKB:  P29475
PHAROS:  P29475
GTEx:  ENSG00000089250 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29475
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
XH8
Query on XH8

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B]
7-(((3-(PYRIDIN-3-YL)PROPYL)AMINO)METHYL)QUINOLIN-2-
C18 H20 N4
SYLCHGGIDVOGEK-UHFFFAOYSA-N
H4B
Query on H4B

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
5,6,7,8-TETRAHYDROBIOPTERIN
C9 H15 N5 O3
FNKQXYHWGSIFBK-RPDRRWSUSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
F [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
XH8 BindingDB:  5VUZ Ki: 108 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 52.14α = 90
b = 122.04β = 90
c = 164.46γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
iMOSFLMdata reduction
Aimlessdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM57353

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-23
    Type: Initial release
  • Version 1.1: 2017-09-06
    Changes: Database references
  • Version 1.2: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description