Journal of Computer-Aided Molecular Design

, Volume 18, Issue 12, pp 739–760

Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design

  • Rajeshri G. Karki
  • Yun Tang
  • Terrence R. BurkeJr
  • Marc C. Nicklaus
Article

DOI: 10.1007/s10822-005-0365-5

Cite this article as:
Karki, R.G., Tang, Y., Burke, T.R. et al. J Comput Aided Mol Des (2004) 18: 739. doi:10.1007/s10822-005-0365-5

Summary

We report structural models of the full-length integrase enzyme (IN) of the human immunodeficiency virus type 1 (HIV-1) and its complex with viral and human DNA. These were developed by means of molecular modeling techniques using all available experimental evidence, including X-ray crystallographic and NMR structures of portions of the full-length protein. Special emphasis was placed on obtaining a model of the enzyme’s active site with the viral DNA apposed to it, based on the hypothesis that such a model would allow structure-based design of inhibitors that retain activity in vivo. This was because bound DNA might be present in vivo after 3’-processing but before strand transfer. These structural models were used to study the potential binding modes of various diketo-acid HIV-1 IN inhibitors (many of them preferentially inhibiting strand transfer) for which no experimentally derived complexed structures are available. The results indicate that the diketo-acid IN inhibitors probably chelate the metal ion in the catalytic site and also prevent the exposure of the 3’-processed end of the viral DNA to human DNA.

Keywords

dockingdrug-designhuman immunodeficiency virusintegrasemolecular modeling

Abbreviations

3′-P

3′-Processing

ABNR

adopted basis Newton-Raphson

ASV-IN

Avian sarcoma virus integrase

DKA

Diketo-acid

HIV-1

human immunodeficiency virus type I

HMG-I (Y)

high mobility group protein isoform I and Y

IN

integrase

LTR

long terminal repeat

MA

matrix protein

MD

molecular dynamics

PR

protease

PDB

Protein Data Bank

RT

reverse transcriptase

SGI

Silicon Graphics, Inc.

SH3

Src-homology 3

ST

strand transfer

rms

root mean square deviation

Vpr

viral protein R

Copyright information

© Springer 2005

Authors and Affiliations

  • Rajeshri G. Karki
    • 1
  • Yun Tang
    • 1
    • 2
  • Terrence R. BurkeJr
    • 1
  • Marc C. Nicklaus
    • 1
  1. 1.Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer InstituteNational Institutes of Health, DHHSFrederickUSA
  2. 2.Department of Medicinal Chemistry, School of PharmacyFudan UniversityShanghaiP. R. China