6BZ2

Crystal structure of wild-type HIV-1 protease with a novel HIV-1 inhibitor GRL-14213A of 6-5-5-ring fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand and 3,5-difluorophenylmethyl as the P1-ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants.

Ghosh, A.K.Rao, K.V.Nyalapatla, P.R.Kovela, S.Brindisi, M.Osswald, H.L.Sekhara Reddy, B.Agniswamy, J.Wang, Y.F.Aoki, M.Hattori, S.I.Weber, I.T.Mitsuya, H.

(2018) ChemMedChem 13: 803-815

  • DOI: https://doi.org/10.1002/cmdc.201700824
  • Primary Citation of Related Structures:  
    6BZ2

  • PubMed Abstract: 

    Herein we report the design, synthesis, X-ray structural, and biological studies of an exceptionally potent HIV-1 protease inhibitor, compound 5 ((3S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl ((2S,3R)-4-((2-(cyclopropylamino)-N-isobutylbenzo[d]thiazole)-6-sulfonamido)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)carbamate). Using structure-based design, we incorporated an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand, and a 3,5-difluorophenylmethyl group as the P1-ligand. The resulting inhibitor 5 exhibited exceptional HIV-1 protease inhibitory and antiviral potency at the picomolar level. Furthermore, it displayed antiviral IC 50 values in the picomolar range against a wide panel of highly multidrug-resistant HIV-1 variants. The inhibitor shows an extremely high genetic barrier against the emergence of drug-resistant variants. It also showed extremely potent inhibitory activity toward dimerization as well as favorable central nervous system penetration. We determined a high-resolution X-ray crystal structure of the complex between inhibitor 5 and HIV-1 protease, which provides molecular insight into the unprecedented activity profiles observed.


  • Organizational Affiliation

    Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907, USA.


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 P03366 (Human immunodeficiency virus type 1 group M subtype B (isolate BH10))
Explore P03366 
Go to UniProtKB:  P03366
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03366
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7OA
Query on 7OA

Download Ideal Coordinates CCD File 
E [auth B](3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl [(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]carbamate
C33 H40 F2 N4 O7 S2
ARWGTMGGJGADTI-VFGYXJDYSA-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
7OA Binding MOAD:  6BZ2 Ki: 0.01 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.67 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.199 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.043α = 90
b = 86.426β = 90
c = 45.932γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
SHELXL-97refinement

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 General Medical Sciences (NIH/NIGMS)United StatesGM53386
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM62920
Ministry of Education, Culture, Sports, Science and Technology (Japan)Japana Grant-in-Aid for Scientific Research (Priority Areas)
Ministry of Health, Welfare, and LaborJapana 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)

Revision History  (Full details and data files)

  • Version 1.0: 2018-02-28
    Type: Initial release
  • Version 1.1: 2018-03-28
    Changes: Data collection, Database references
  • Version 1.2: 2018-05-02
    Changes: Data collection, Database references
  • Version 1.3: 2020-01-01
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description