title: A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase.
abstract: BACKGROUND
  Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are vital in treating HIV-1 infection by inhibiting reverse transcriptase (RT). Drug toxicity and resistance drive the need for effective new inhibitors with improved physiochemical properties and potent antiviral activity. Computer-aided and structure-based drug design have guided the addition of solubilizing substituents to the diaryltriazine scaffold. These derivatives have markedly improved solubility and maintain low nanomolar antiviral activity against RT. The molecular and structural basis of inhibition for this series was determined to facilitate future inhibitor development with improved pharmacological profiles.
  
  
  METHODS
  The molecular mechanism of inhibition was investigated using transient-state kinetic analysis. Crystal structures of RT in complex with each inhibitor were obtained to investigate the structural basis of inhibition.
  
  
  RESULTS
  The diaryltriazine and its morpholine derivative have RT inhibition constants of 9±2nM and 14±4nM, respectively. They adopt differential binding modes within the non-nucleoside inhibitor binding pocket to distort the catalytic site geometry and primer grip regions. The novel morpholinopropoxy substituent extends into the RT/solvent interface of the NNIBP.
  
  
  CONCLUSIONS
  Kinetic and structural analyses show that these inhibitors behave as conventional NNRTIs and inhibit the polymerization step. This study confirms that appending solubilizing substituents on the azine ring of diaryltriazine class of NNRTIs that extend into the RT/solvent interface effectively maintains low nanomolar potency and improves physiochemical properties.
  
  
  CONCLUSIONS
  The modification of NNRTI scaffolds with solubilizing substituents, which extend into the RT/solvent interface, yields potent antivirals and is an effective strategy for developing novel inhibitors with improved pharmacological properties.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Mislak
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Frey
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Mariela
authors.initials: M
authors.lastname: Bollini
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA. Electronic address: Karen.Anderson@yale.edu.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D055595:Mechanical Phenomena; D009025:Morpholines / Q000737:chemistry; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D014227:Triazines / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D009025:Morpholines; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; C037574:morpholine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Crystallography; HIV-1; NNRTI; Reverse transcriptase; Transient kinetics
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