6RX6

Trypanosoma brucei PTR1 (TbPTR1) in complex with inhibitor 4 (NMT-C0026)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.11 Å
  • R-Value Free: 0.132 
  • R-Value Work: 0.115 
  • R-Value Observed: 0.116 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1.

Pohner, I.Quotadamo, A.Panecka-Hofman, J.Luciani, R.Santucci, M.Linciano, P.Landi, G.Di Pisa, F.Dello Iacono, L.Pozzi, C.Mangani, S.Gul, S.Witt, G.Ellinger, B.Kuzikov, M.Santarem, N.Cordeiro-da-Silva, A.Costi, M.P.Venturelli, A.Wade, R.C.

(2022) J Med Chem 65: 9011-9033

  • DOI: https://doi.org/10.1021/acs.jmedchem.2c00232
  • Primary Citation of Related Structures:  
    6RX0, 6RX5, 6RX6, 6RXC

  • PubMed Abstract: 

    The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC 50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.


  • Organizational Affiliation

    Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), D-69118 Heidelberg, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pteridine reductase
A, B, C, D
288Trypanosoma brucei bruceiMutation(s): 0 
Gene Names: PTR1
UniProt
Find proteins for O76290 (Trypanosoma brucei brucei)
Explore O76290 
Go to UniProtKB:  O76290
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO76290
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP

Download Ideal Coordinates CCD File 
E [auth A],
G [auth B],
J [auth C],
L [auth D]
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
KMK (Subject of Investigation/LOI)
Query on KMK

Download Ideal Coordinates CCD File 
F [auth A],
H [auth B],
K [auth C],
M [auth D]
methyl 1-[4-[[2,4-bis(azanyl)pteridin-6-yl]methyl-(3-oxidanylpropyl)amino]phenyl]carbonylpiperidine-4-carboxylate
C24 H30 N8 O4
NKRKEQBTIYLTPA-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
I [auth B]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
KMK BindingDB:  6RX6 IC50: 30 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.11 Å
  • R-Value Free: 0.132 
  • R-Value Work: 0.115 
  • R-Value Observed: 0.116 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.76α = 90
b = 90.64β = 115.74
c = 82.96γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Union603240

Revision History  (Full details and data files)

  • Version 1.0: 2020-07-15
    Type: Initial release
  • Version 1.1: 2023-09-13
    Changes: Data collection, Database references, Refinement description
  • Version 1.2: 2024-01-24
    Changes: Refinement description