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Fragment Screening and HIV Therapeutics

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Fragment-Based Drug Discovery and X-Ray Crystallography

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 317))

Abstract

Fragment screening has proven to be a powerful alternative to traditional methods for drug discovery. Biophysical methods, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance, are used to screen a diverse library of small molecule compounds. Although compounds identified via this approach have relatively weak affinity, they provide a good platform for lead development and are highly efficient binders with respect to their size. Fragment screening has been utilized for a wide range of targets, including HIV-1 proteins. Here, we review the fragment screening studies targeting HIV-1 proteins using X-ray crystallography or surface plasmon resonance. These studies have successfully detected binding of novel fragments to either previously established or new sites on HIV-1 protease and reverse transcriptase. In addition, fragment screening against HIV-1 reverse transcriptase has been used as a tool to better understand the complex nature of ligand binding to a flexible target.

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Abbreviations

AIDS:

Acquired immune deficiency syndrome

ClogP:

Calculated logarithm of octanol–water partition coefficient

HAART:

Highly active antiretroviral therapy

HIV:

Human immunodeficiency virus

IC50 :

Concentration of a compound leading to 50% enzyme inhibition

IN:

Integrase

ITC:

Isothermal calorimetry

K D :

Dissociation constant

LE:

Ligand efficiency

MS:

Mass spectroscopy

NMR:

Nuclear magnetic resonance

NNRTI:

Non-nucleoside reverse transcriptase inhibitor

NRTI:

Nucleoside/nucleotide reverse transcriptase inhibitor

PR:

Protease

RT:

Reverse transcriptase

SPR:

Surface plasmon resonance

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Authors and Affiliations

  1. Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Department of Medicinal Chemistry, Rutgers University, Piscataway, NJ, USA

    Joseph D. Bauman, Disha Patel & Eddy Arnold

Authors
  1. Joseph D. Bauman
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  2. Disha Patel
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  3. Eddy Arnold
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Corresponding author

Correspondence to Eddy Arnold .

Editor information

Editors and Affiliations

  1. Astex Pharmaceuticals, Milton Road, Cambridge, CB4 0QA, United Kingdom

    Thomas G. Davies

  2. , Department of Biochemistry, University of Cambridge, Tennis Court Road 80, Cambridge, CB2 1GA, United Kingdom

    Marko Hyvönen

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© 2011 Springer-Verlag Berlin Heidelberg

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Bauman, J.D., Patel, D., Arnold, E. (2011). Fragment Screening and HIV Therapeutics. In: Davies, T., Hyvönen, M. (eds) Fragment-Based Drug Discovery and X-Ray Crystallography. Topics in Current Chemistry, vol 317. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2011_232

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