6DV4

HIV-1 wild type protease with GRL-04315A, a tetrahydronaphthalene carboxamide with (R)-Boc-amine and (S)-hydroxyl functionalities as the P2 ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.14 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.173 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands.

Ghosh, A.K.Jadhav, R.D.Simpson, H.Kovela, S.Osswald, H.Agniswamy, J.Wang, Y.F.Hattori, S.I.Weber, I.T.Mitsuya, H.

(2018) Eur J Med Chem 160: 171-182

  • DOI: https://doi.org/10.1016/j.ejmech.2018.09.046
  • Primary Citation of Related Structures:  
    6DV0, 6DV4

  • PubMed Abstract: 

    We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.


  • Organizational Affiliation

    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907, United States. 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 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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GA5 (Subject of Investigation/LOI)
Query on GA5

Download Ideal Coordinates CCD File 
E [auth B]tert-butyl [(1R,4S)-4-hydroxy-7-{[(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamoyl}-1,2,3,4-tetrahydronaphthalen-1-yl]carbamate
C37 H49 N3 O8 S
CBAMANYQGALFBH-ALMGMPQLSA-N
GOL
Query on GOL

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

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

Download Ideal Coordinates CCD File 
D [auth A],
F [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
GA5 Binding MOAD:  6DV4 Ki: 1.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.14 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.173 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.755α = 90
b = 86.229β = 90
c = 46.181γ = 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 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
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: 2018-10-31
    Type: Initial release
  • Version 1.1: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description