6E9A

HIV-1 WILD TYPE PROTEASE WITH GRL-034-17A, (3aS, 5R, 6aR)-2-OXOHEXAHYD CYCLOPENTA[D]-5-OXAZOLYL URETHANE WITH A BICYCLIC OXAZOLIDINONE SCAFF AS THE P2 LIGAND


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.22 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies.

Ghosh, A.K.Williams, J.N.Ho, R.Y.Simpson, H.M.Hattori, S.I.Hayashi, H.Agniswamy, J.Wang, Y.F.Weber, I.T.Mitsuya, H.

(2018) J Med Chem 61: 9722-9737

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01227
  • Primary Citation of Related Structures:  
    6E7J, 6E9A

  • PubMed Abstract: 

    We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme K i of 40 pM and antiviral IC 50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.


  • Organizational Affiliation

    Department of Chemistry and Department of Medicinal Chemistry , Purdue University , 560 Oval Drive , West Lafayette , Indiana 47907 , United States.


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 P04585 (Human immunodeficiency virus type 1 group M subtype B (isolate HXB2))
Explore P04585 
Go to UniProtKB:  P04585
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04585
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
J0S
Query on J0S

Download Ideal Coordinates CCD File 
E [auth B](3aS,5R,6aR)-2-oxohexahydro-2H-cyclopenta[d][1,3]oxazol-5-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate
C28 H37 N3 O8 S
SUKOCHXFOBSBBB-MMXJFWRNSA-N
FMT
Query on FMT

Download Ideal Coordinates CCD File 
H [auth B]FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
CL
Query on CL

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

Download Ideal Coordinates CCD File 
C [auth A],
F [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
J0S Binding MOAD:  6E9A Ki: 1.20e-3 (nM) from 1 assay(s)
BindingDB:  6E9A Ki: 1.20e-3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.22 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.372α = 90
b = 86.276β = 90
c = 46.02γ = 90
Software Package:
Software NamePurpose
SHELXL-97refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

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 Allergy and Infectious Diseases (NIH/NIAID)United StatesGM53386
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesGM62920
National Institutes of Health/National Cancer Institute (NIH/NCI)United Statesthe Intramural Research Program of the Center for Cancer Research
Department of Energy (DOE, United States)United StatesW-31-109-Eng-38
National Institutes of Health/National Cancer Institute (NIH/NCI)United Statesthe Intramural Research Program of the Center for Cancer Research
Ministry of Education, Culture, Sports, Science and Technology (Japan)Japana Grant-in-Aid for Scientific Research (Priority Areas)
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)

Revision History  (Full details and data files)

  • Version 1.0: 2018-11-07
    Type: Initial release
  • Version 1.1: 2018-11-21
    Changes: Data collection, Database references
  • Version 1.2: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description