4UPJ

HUMAN IMMUNODEFICIENCY VIRUS TYPE 2 PROTEASE MUTANT WITH LYS 57 REPLACED BY LEU (K57L) COMPLEX WITH U097410 [4-HYDROXY-3-[1-[3-[[[[(TERT-BUTYLOXYCARBONYL) AMINOMETHYL]CARBONYL]AMINO]PHENYL]PROPYL]COUMARIN


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.206 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors.

Thaisrivongs, S.Watenpaugh, K.D.Howe, W.J.Tomich, P.K.Dolak, L.A.Chong, K.-T.Tomich, C.-S.C.Tomasselli, A.G.Turner, S.R.Strohbach, J.W.Mulichak, A.M.Janakiraman, M.N.Moon, J.B.Lynn, J.C.Horng, M.-M.Hinshaw, R.R.Curry, K.A.Rothrock, D.J.

(1995) J Med Chem 38: 3624-3637

  • DOI: https://doi.org/10.1021/jm00018a023
  • Primary Citation of Related Structures:  
    1UPJ, 2UPJ, 3UPJ, 4UPJ

  • PubMed Abstract: 

    The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover nonpeptidic HIV protease inhibitors had previously identified compound II (phenprocoumon, K(i) = 1 muM) as a lead template. Crystal structures of HIV protease complexes containing the peptide-derived inhibitor I (1-(naphthoxyacetyl)-L-histidyl-5(S)-amino-6-cyclohexyl-3 (R),4(R)-dihydroxy-2(R)-isopropylhexanoyl-L-isoleucine N-(2-pyridylmethyl)amide) and nonpeptidic inhibitors, such as phenprocoumon (compound II), provided a rational basis for the structure-based design of more active analogues. This investigation reports on the important finding of a carboxamide functionally appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone templates which resulted in a new promising series of nonpeptidic HIV protease inhibitors with improved enzyme-binding affinity. The most active diastereomer of the carboxamide-containing compound XXIV inhibited HIV-1 protease with a K(i) value of 0.0014 muM. This research provides a new design direction for the discovery of more potent HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.


  • Organizational Affiliation

    Upjohn Laboratories, Kalamazoo, Michigan 49001, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-2 PROTEASE
A, B
99Human immunodeficiency virus 2Mutation(s): 1 
EC: 3.4.23.16
UniProt
Find proteins for P04584 (Human immunodeficiency virus type 2 subtype A (isolate ROD))
Explore P04584 
Go to UniProtKB:  P04584
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04584
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
U04
Query on U04

Download Ideal Coordinates CCD File 
C [auth A]({3-[1-(4-HYDROXY-2-OXO-2H-CHROMEN-3-YL)-PROPYL]-PHENYLCARBAMOYL}-METHYL)-CARBAMIC ACID TERT-BUTYL ESTER
C25 H28 N2 O6
QUQQVMVIWCUYFV-KRWDZBQOSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
U04 Binding MOAD:  4UPJ Ki: 160 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Work: 0.206 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 31.128α = 90
b = 45.312β = 90
c = 132.735γ = 90
Software Package:
Software NamePurpose
MERLOTphasing
CEDARrefinement
XENGENdata reduction
XENGENdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1996-10-14
    Type: Initial release
  • Version 1.1: 2008-03-25
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2012-02-22
    Changes: Database references
  • Version 1.4: 2021-11-03
    Changes: Database references, Derived calculations
  • Version 1.5: 2024-02-28
    Changes: Data collection