3DRP

HIV reverse transcriptase in complex with inhibitor R8e


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses.

Tucker, T.J.Sisko, J.T.Tynebor, R.M.Williams, T.M.Felock, P.J.Flynn, J.A.Lai, M.T.Liang, Y.McGaughey, G.Liu, M.Miller, M.Moyer, G.Munshi, V.Perlow-Poehnelt, R.Prasad, S.Reid, J.C.Sanchez, R.Torrent, M.Vacca, J.P.Wan, B.L.Yan, Y.

(2008) J Med Chem 51: 6503-6511

  • DOI: https://doi.org/10.1021/jm800856c
  • Primary Citation of Related Structures:  
    3DRP, 3DRR, 3DRS

  • PubMed Abstract: 

    Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.


  • Organizational Affiliation

    Departments of Medicinal Chemistry and Structural Biology, Merck Research Laboratories, WP14-3, 770 Sumneytown Pike, P.O. Box 4, West Point, PennsylVania 19486-0004, USA. tom_tucker@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Reverse transcriptase/ribonuclease H563HIV-1 M:B_HXB2RMutation(s): 0 
Gene Names: gag-pol
EC: 2.7.7.49 (PDB Primary Data), 2.7.7.7 (PDB Primary Data), 3.1.26.4 (PDB Primary Data)
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
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
p51 RT443HIV-1 M:B_HXB2RMutation(s): 0 
Gene Names: gag-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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
R8E
Query on R8E

Download Ideal Coordinates CCD File 
C [auth A]3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile
C20 H13 Cl2 N5 O2
KXDIHAQCVNNLIB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
R8E PDBBind:  3DRP IC50: 0.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.191 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 118.86α = 90
b = 155.03β = 90
c = 155.54γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
ADSCdata collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-10-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description