1T7I

The structural and thermodynamic basis for the binding of TMC114, a next-generation HIV-1 protease inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.163 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor

Surleraux, D.L.N.G.Tahri, A.Verschueren, W.G.Pille, G.M.E.de Kock, H.A.Jonckers, T.H.M.Peeters, A.De Meyer, S.Azijn, H.Pauwels, R.de Bethune, M.-P.King, N.M.Prabu-Jeyabalan, M.Schiffer, C.A.Wigerinck, P.B.T.P.

(2005) J Med Chem 48: 1813-1822

  • DOI: https://doi.org/10.1021/jm049560p
  • Primary Citation of Related Structures:  
    1T3R, 1T7I, 1T7J

  • PubMed Abstract: 

    The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.


  • Organizational Affiliation

    Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Pol Polyprotein
A, B
99Human immunodeficiency virus 1Mutation(s): 4 
Gene Names: POL
EC: 3.4.23.16
UniProt
Find proteins for P35963 (Human immunodeficiency virus type 1 group M subtype B (isolate YU-2))
Explore P35963 
Go to UniProtKB:  P35963
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35963
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
017 BindingDB:  1T7I Ki: min: 2.00e-4, max: 2 (nM) from 16 assay(s)
Kd: 0.02 (nM) from 1 assay(s)
IC50: min: 0.06, max: 370 (nM) from 10 assay(s)
EC50: min: 0.25, max: 112 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.35 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.163 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.858α = 90
b = 58.04β = 90
c = 61.656γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-05-10
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2021-10-27
    Changes: Database references, Derived calculations, Structure summary
  • Version 1.4: 2023-08-23
    Changes: Data collection, Refinement description