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Current Pharmaceutical Design
ISSN (Print): 1381-6128
ISSN (Online): 1873-4286
VOLUME: 20
ISSUE: 5
DOI: 10.2174/138161282005140214163439      Price:  $58









Structure-based Design of Conformationally Flexible Reverse Transcriptase Inhibitors to Combat Resistant HIV

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Author(s): Ge-Fei Hao, Sheng-Gang Yang and Guang-Fu Yang
Pages 725-739 (15)
Abstract:
Reverse transcriptase (RT) is one of the most important targets for HIV drug discovery. However, the emergence of resistant mutants has become one of the biggest challenges in HIV-1 RT drug discovery/development and attracted great research interests worldwide. It is particularly important to develop novel anti-HIV-1 RT agents that have improved potency and efficacy against the wild-type (WT) RT, but also target resistant RT forms. Previous crystal complex structures of HIV-1 RT revealed the interaction mechanism between the enzyme and inhibitors, which promoted the exploitation of inhibitor that had sufficient conformational flexibility to combat resistance. Hence, the potential flexibility of a drug should be part of the strategy considered in the early stages of designing drugs that are intended to be broadly effective against mutated targets associated with drug resistance. This review provides an overview of the state of the art in this field, including design strategies and challenges for medicinal chemists.
Keywords:
HIV Reverse transcriptase, conformational flexibility, drug resistance.
Affiliation:
College of Chemistry, Central China Normal University, Luoyu Road 152, Wuhan 430079, Hubei Province, P.R. China.