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

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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.

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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

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Authors and Affiliations

  1. Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, 376 Boyles Street, Frederick, MD, 21702, USA

    Rajeshri G. Karki, Yun Tang, Terrence R. Burke Jr & Marc C. Nicklaus

  2. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 138 Yiueyuan Road, Shanghai, 200031, P. R. China

    Yun Tang

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  1. Rajeshri G. Karki
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Karki, R.G., Tang, Y., Burke, T.R. et al. Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design. J Comput Aided Mol Des 18, 739–760 (2004). https://doi.org/10.1007/s10822-005-0365-5

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  • DOI: https://doi.org/10.1007/s10822-005-0365-5

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