4Z1K

Carbonic anhydrase inhibitors: Design and synthesis of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms (hCA VII, hCA IX, and hCA XIV)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.170 
  • R-Value Work: 0.134 
  • R-Value Observed: 0.136 

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Ligand Structure Quality Assessment 


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Literature

Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms.

Buemi, M.R.De Luca, L.Ferro, S.Bruno, E.Ceruso, M.Supuran, C.T.Pospisilova, K.Brynda, J.Rezacova, P.Gitto, R.

(2015) Eur J Med Chem 102: 223-232

  • DOI: https://doi.org/10.1016/j.ejmech.2015.07.049
  • Primary Citation of Related Structures:  
    4Z0Q, 4Z1E, 4Z1J, 4Z1K, 4Z1N

  • PubMed Abstract: 

    A set of heteroaryl-N-carbonylbenzenesulfonamides has been designed, synthesized, and screened as inhibitors of human carbonic anhydrases (hCAs). The new sulfonamide derivatives were tested against hCA I, hCA II, hCA VII, hCA IX, and hCA XII isoforms using acetazolamide (AAZ, 1) and topiramate (TPM, 2) as reference compounds. Six compounds were low nanomolar inhibitors of tumor-associated hCA IX isoform (Ki values < 10 nM); among them we identified three arylsulfonamides showing unexpected inefficacy over brain distributed hCA VII isoform (hCA IX/hCA VII selectivity ratio > 1500 for compound 5c). Thus, these compounds can offer the opportunity to highlight the interactions preventing the inhibition of hCA VII mainly expressed in central nervous system. Thereby, we used structural and computational techniques to study in depth the interaction with hCAs. In an effort to confirm the inhibitory action we determined crystal structures of five selected heteroaryl-N-carbonylbenzenesulfonamides (4a, 4b, 4e, 5c, and 5e) in complex with hCA II. Moreover, to explore the lack of inhibitory effects of selected compounds (e.g.4b and 5c) we also performed docking studies into hCA VII catalytic site.


  • Organizational Affiliation

    Dipartimento Scienze del Farmaco e dei Prodotti per la salute, Università degli Studi di Messina, Viale Annunziata, I-98168 Messina, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Carbonic anhydrase 2257Homo sapiensMutation(s): 0 
Gene Names: CA2
EC: 4.2.1.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00918 (Homo sapiens)
Explore P00918 
Go to UniProtKB:  P00918
PHAROS:  P00918
GTEx:  ENSG00000104267 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00918
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4KB
Query on 4KB

Download Ideal Coordinates CCD File 
C [auth A]4-[(6,7-dihydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]benzenesulfonamide
C16 H16 N2 O5 S
IPKFBGPSWRSLEJ-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4KB Binding MOAD:  4Z1K Ki: 4.7 (nM) from 1 assay(s)
BindingDB:  4Z1K Ki: 4.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.170 
  • R-Value Work: 0.134 
  • R-Value Observed: 0.136 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.141α = 90
b = 41.259β = 104.43
c = 72.095γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
REFMACphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
GACRCzech RepublicGA15-05677S
Technology Agency of the Czech RepublicCzech RepublicTE01020028

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-26
    Type: Initial release