2WKZ

HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimic with Improved Cell-Based Antiviral Activity


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.229 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells.

Mahalingam, A.K.Axelsson, L.Ekegren, J.K.Wannberg, J.Kihlstr, J.Unge, T.Wallberg, H.Samuelsson, B.Larhed, M.Hallberg, A.

(2010) J Med Chem 53: 607

  • DOI: https://doi.org/10.1021/jm901165g
  • Primary Citation of Related Structures:  
    2WKZ, 2WL0

  • PubMed Abstract: 

    By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTEASE
A, B
99Human immunodeficiency virus type 1 (Z2/CDC-Z34 ISOLATE)Mutation(s): 0 
EC: 3.4.23.16
UniProt
Find proteins for P12499 (Human immunodeficiency virus type 1 group M subtype D (isolate Z2/CDC-Z34))
Explore P12499 
Go to UniProtKB:  P12499
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12499
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5AH
Query on 5AH

Download Ideal Coordinates CCD File 
C [auth B]METHYL [(1S)-1-({2-[(3S)-3-BENZYL-3-HYDROXY-4-{[(1S,2R)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL]AMINO}-4-OXOBUTYL]-2-(4-PYRIDIN-2-YLBENZYL)HYDRAZINO}CARBONYL)-2,2-DIMETHYLPROPYL]CARBAMATE
C40 H47 N5 O6
AWOPQBWUWCOWJO-UKVDXBKXSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5AH Binding MOAD:  2WKZ Ki: 1.7 (nM) from 1 assay(s)
BindingDB:  2WKZ Ki: 1.7 (nM) from 1 assay(s)
PDBBind:  2WKZ Ki: 1.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.229 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.42α = 90
b = 86.08β = 90
c = 46.51γ = 90
Software Package:
Software NamePurpose
CNSrefinement
MOSFLMdata reduction
CCP4data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-12-15
    Type: Initial release
  • Version 1.1: 2014-03-12
    Changes: Database references, Source and taxonomy, Structure summary, Version format compliance
  • Version 1.2: 2018-01-17
    Changes: Data collection
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description