title: Structure-based design of conformationally flexible reverse transcriptase inhibitors to combat resistant HIV.
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.
authors.forename: Ge-Fei
authors.initials: GF
authors.lastname: Hao
authors.forename: Sheng-Gang
authors.initials: SG
authors.lastname: Yang
authors.affiliation: College of Chemistry, Central China Normal University, Luoyu Road 152, Wuhan 430079, Hubei Province, P.R. China. gfyang@mail.ccnu.edu.cn.
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D024882:Drug Resistance, Viral; D015507:Drugs, Investigational / Q000737:chemistry / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D055595:Mechanical Phenomena; D008958:Models, Molecular; D008968:Molecular Conformation; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018583:Pliability; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D015507:Drugs, Investigational; D050505:Mutant Proteins; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase