5WLO

a novel 13-ring macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

  • Classification: hydrolase/hydrolase inhibitor
  • Organism(s): Human immunodeficiency virus 1
  • Expression System: Escherichia coli
  • Mutation(s): Yes 

  • Deposited: 2017-07-27 Released: 2017-10-11 
  • Deposition Author(s): Wang, Y.-F., Agniswamy, J., Weber, I.T.
  • Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), National Institutes of Health/National Cancer Institute (NIH/NCI), Ministry of Education, Culture, Sports, Science and Technology (Japan), Ministry of Health,Labour and Welfare (Japan), National Institutes of Health/National Center for Research Resources (NIH/NCRR)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.27 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.159 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands.

Ghosh, A.K.Sean Fyvie, W.Brindisi, M.Steffey, M.Agniswamy, J.Wang, Y.F.Aoki, M.Amano, M.Weber, I.T.Mitsuya, H.

(2017) Bioorg Med Chem Lett 27: 4925-4931

  • DOI: https://doi.org/10.1016/j.bmcl.2017.09.003
  • Primary Citation of Related Structures:  
    5WLO

  • PubMed Abstract: 

    Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (K i =13.2nM, IC 50 =22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (K i =62pM and 14pM, respectively) and antiviral activity (IC 50 =5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.


  • Organizational Affiliation

    Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. Electronic address: akghosh@purdue.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protease
A, B
99Human immunodeficiency virus 1Mutation(s): 5 
Gene Names: pol
UniProt
Find proteins for Q72498 (Human immunodeficiency virus 1)
Explore Q72498 
Go to UniProtKB:  Q72498
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ72498
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GR7 (Subject of Investigation/LOI)
Query on GR7

Download Ideal Coordinates CCD File 
F [auth B](3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(2S,3R)-3-hydroxy-4-[(7E)-13-methoxy-1,1-dioxo-1,4,5,6,9,11-hexahydro-10,1lambda~6~,2-benzoxathiazacyclotridecin-2(3H)-yl]-1-phenylbutan-2-yl}carbamate
C32 H42 N2 O9 S
QVQZOHIOYHJWJV-RSNMJCISSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
J [auth B]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
K [auth B]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
G [auth B],
H [auth B],
I [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
GR7 Binding MOAD:  5WLO Ki: 0.01 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.27 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.159 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.475α = 90
b = 86.034β = 90
c = 45.877γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
SHELXLrefinement

Structure Validation

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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 StatesGM53386
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM62920
National Institutes of Health/National Cancer Institute (NIH/NCI)United States--
Ministry of Education, Culture, Sports, Science and Technology (Japan)Japana Grant-in-Aid for Scientific Research (Priority Areas)
Ministry of Health,Labour and Welfare (Japan)Japana Grant for Promotion of AIDS Research
Ministry of Education, Culture, Sports, Science and Technology (Japan)Japanthe Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo)
National Institutes of Health/National Center for Research Resources (NIH/NCRR)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2017-10-11
    Type: Initial release
  • Version 1.1: 2017-10-18
    Changes: Author supporting evidence
  • Version 1.2: 2017-10-25
    Changes: Database references
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description