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Fragment Screening and HIV Therapeutics

  • Joseph D. Bauman
  • Disha Patel
  • Eddy Arnold
Chapter
Part of the Topics in Current Chemistry book series (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.

Keywords

Drug design Fragment screening HIV Protease Reverse transcriptase Surface plasmon resonance X-ray crystallography 

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

KD

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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Copyright information

© Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Department of Medicinal ChemistryRutgers UniversityPiscatawayUSA

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