Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities

Abstract

Introduction: The search for additional drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery.

Areas covered: In this critical review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compounds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress.

Expert opinion: Rapid progress in biophysical detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallographic overlays, fragment growth exploiting dynamic combinatorial chemistry, and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.

Keywords:

• AIDS
• drug design
• fragment-based drug design
• HIV
• medicinal chemistry
• protease
• reverse transcriptase

Acknowledgements

All the figures of binding modes were generated using PyMol (www.pymol.org).

Declaration of interest

The authors are supported by grants from the National Natural Science Foundation of China (NSFC No. 81573347, 81102320 and 81273354), the Key Project of NSFC for International Cooperation (grant no. 81420108027), the Research Fund for the Doctoral Program of Higher Education of China (grant no. 20110131130005 and 20110131120037) and the Science and Technology Development Project of Shandong Province (grant no. 2014GSF118012). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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