9GCX

Crystal structure of bovine Cytochrome bc1 in complex with inhibitor F8


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.52 ?
  • R-Value Free: 0.241 
  • R-Value Work: 0.188 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties.

Ge, S.Jian, R.Xuan, Q.Zhu, Y.Ren, X.Li, W.Chen, X.Huang, R.K.Lee, C.S.Leung, S.C.Basilico, N.Parapini, S.Taramelli, D.Pinthong, N.Antonyuk, S.V.O'Neill, P.M.Sheng, Z.Hong, W.D.

(2024) Eur J Med Chem 284: 117228-117228

  • DOI: https://doi.org/10.1016/j.ejmech.2024.117228
  • Primary Citation of Related Structures:  
    9GCX

  • PubMed Abstract: 

    Aryl quinolone derivatives can target the cytochrome bc 1 complex of Plasmodium falciparum, exhibiting excellent in vitro and in vivo antimalarial activity. However, their clinical development has been hindered due to their poor aqueous solubility profiles. In this study, a series of bioisosteres containing saturated heterocycles fused to a 4-pyridone ring were designed to replace the inherently poorly soluble quinolone core in antimalarial quinolones with the aim to reduce ¦Ð-¦Ð stacking interactions in the crystal packing solid state, and a synthetic route was developed to prepare these alternative core derivatives. One such novel derivate, F14, exhibited significant enhancements in both aqueous solubility (20?¦ÌM) and lipophilicity (LogD 2.7), whilst retaining nanomolar antimalarial activity against the W2 strain of P. falciparum (IC 50 ?=?235?nM). The pharmacokinetic studies reported, provide preliminary insights into the in vivo distribution and elimination of F14, while findings from single crystal X-ray diffraction experiment rationalized the enhanced solubility. Protein X-ray crystallography and in silico docking simulations provide insight into the potential mode of action within the cytochrome bc 1 complex. These findings demonstrated the viability of this bioisostere replacement strategy and provided support for further exploration of in vivo efficacy in preclinical animal models and valuable insights for new drug design strategies in the fight against malaria.


  • Organizational Affiliation

    School of Pharmacy and Food Engineering, Wuyi University, 529020, Jiangmen, China; Department of Chemistry, University of Liverpool, L69 7ZD, Liverpool, UK; Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region of China.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit 1, mitochondrial480Bos taurusMutation(s): 0 
UniProt
Find proteins for P31800 (Bos taurus)
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UniProt GroupP31800
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit 2, mitochondrial453Bos taurusMutation(s): 0 
UniProt
Find proteins for P23004 (Bos taurus)
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UniProt GroupP23004
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b379Bos taurusMutation(s): 0 
UniProt
Find proteins for P00157 (Bos taurus)
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UniProt GroupP00157
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome c1, heme protein, mitochondrial325Bos taurusMutation(s): 0 
EC: 7.1.1.8
UniProt
Find proteins for P00125 (Bos taurus)
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UniProt GroupP00125
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Entity ID: 5
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit Rieske, mitochondrial
E, I
274Bos taurusMutation(s): 0 
EC: 1.10.2.2 (PDB Primary Data), 7.1.1.8 (UniProt)
UniProt
Find proteins for P13272 (Bos taurus)
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UniProt GroupP13272
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Entity ID: 6
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit 7111Bos taurusMutation(s): 0 
UniProt
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UniProt GroupP00129
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Entity ID: 7
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit 882Bos taurusMutation(s): 0 
UniProt
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UniProt GroupP13271
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Entity ID: 8
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit 6, mitochondrial109Bos taurusMutation(s): 0 
UniProt
Find proteins for A0A452DIC1 (Bos taurus)
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UniProt GroupA0A452DIC1
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Entity ID: 9
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit 964Bos taurusMutation(s): 0 
UniProt
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Entity ID: 10
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome b-c1 complex subunit 1056Bos taurusMutation(s): 0 
UniProt
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UniProt GroupP07552
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Small Molecules
Ligands 9 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CDL
Query on CDL

Download Ideal Coordinates CCD File 
M [auth A],
Q [auth C],
W [auth D]
CARDIOLIPIN
C81 H156 O17 P2
XVTUQDWPJJBEHJ-KZCWQMDCSA-L
PSC
Query on PSC

Download Ideal Coordinates CCD File 
Z [auth E](7R,17E,20E)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSA-17,20-DIEN-1-AMINIUM 4-OXIDE
C42 H81 N O8 P
JLPULHDHAOZNQI-AUSZDXHESA-O
LOP
Query on LOP

Download Ideal Coordinates CCD File 
BA [auth G]
L [auth A]
P [auth C]
S [auth C]
T [auth C]
BA [auth G],
L [auth A],
P [auth C],
S [auth C],
T [auth C],
Y [auth E]
(1R)-2-{[(R)-(2-AMINOETHOXY)(HYDROXY)PHOSPHORYL]OXY}-1-[(DODECANOYLOXY)METHYL]ETHYL (9Z)-OCTADEC-9-ENOATE
C35 H68 N O8 P
FUUNMZKPCMPCHT-ILGKRYBBSA-N
HEC
Query on HEC

Download Ideal Coordinates CCD File 
V [auth D]HEME C
C34 H34 Fe N4 O4
HXQIYSLZKNYNMH-LJNAALQVSA-N
HEM
Query on HEM

Download Ideal Coordinates CCD File 
N [auth C],
O [auth C]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
LMT
Query on LMT

Download Ideal Coordinates CCD File 
U [auth C]DODECYL-BETA-D-MALTOSIDE
C24 H46 O11
NLEBIOOXCVAHBD-QKMCSOCLSA-N
A1IKG
Query on A1IKG

Download Ideal Coordinates CCD File 
R [auth C]2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-1,5,7,8-tetrahydro-4H-pyrano[4,3-b]pyridin-4-one
C22 H18 F3 N O4
KAKRHIRXYVSXMS-FQEVSTJZSA-N
FES
Query on FES

Download Ideal Coordinates CCD File 
X [auth E]FE2/S2 (INORGANIC) CLUSTER
Fe2 S2
NIXDOXVAJZFRNF-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth F],
CA [auth G],
DA [auth G]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.52 ?
  • R-Value Free: 0.241 
  • R-Value Work: 0.188 
  • Space Group: P 65 2 2
Unit Cell:
Length ( ? )Angle ( ? )
a = 210.082¦Á = 90
b = 210.082¦Â = 90
c = 344.844¦Ã = 120
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2025-01-22
    Type: Initial release
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