title: Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Shandong University, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry , 44 West Culture Road, 250012, Jinan, Shandong, China zhanpeng1982@sdu.edu.cn , xinyongl@sdu.edu.cn.
authors.forename: Boshi
authors.initials: B
authors.lastname: Huang
authors.affiliation: a Shandong University, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry , 44 West Culture Road, 250012, Jinan, Shandong, China zhanpeng1982@sdu.edu.cn , xinyongl@sdu.edu.cn.
authors.forename: Dongwei
authors.initials: D
authors.lastname: Kang
authors.affiliation: a Shandong University, School of Pharmaceutical Sciences, Key Laboratory of Chemical Biology (Ministry of Education), Department of Medicinal Chemistry , 44 West Culture Road, 250012, Jinan, Shandong, China zhanpeng1982@sdu.edu.cn , xinyongl@sdu.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods / Q000639:trends; D024921:Drug Resistance, Multiple, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D014764:Viral Proteins
keywords: AIDS; HIV; drug design; fragment-based drug design; medicinal chemistry; protease; reverse transcriptase