Conformational properties of nucleotide-based template-competitive HIV-1 reverse transcriptase inhibitors

Analysis of enzyme binding modes

Weiying Lin, Ke Li, Bob Moore, Michael B. Doughty

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Nucleotides 2-(4-azidophenacyl)thio-1,N6-etheno-2′-deoxyadenosine 5′-triphosphate 1 and its tetrafluoro analog 2 inhibit HIV-1 reverse transcriptase (RT) competitively relative to template. These template-competitive RT inhibitors (TCRTIs) were analyzed for conformational properties by molecular modeling and NMR analysis. Both inhibitors prefer sugar conformations of C2′endo/C3′-exo with a high-anti glycosidic bond rotation and +sc/ap phosphate conformation (γ). The major effect of the etheno group is to favor an extended, fully staggered anti conformation in the N1-C2-S-CH2 ψ1 side chain rotation, and NMR analysis detects a long range sugar H4′ to side chain phenyl meta-H NOE, a result consistent with this compact structure as an important contributor to the solution structure. The binding model generated places the phenyl side chain in a lipophilic pocket in the template grip region of the RT polymerase domain with the Mg-triphosphate complexed to active site carboxylates. The structures of the TCRTIs are compared with that of the template-competitive DNA polymerase inhibitor 2-(4-azidophenacyl)thio-2′-dcoxyadeno sine 5′-triphosphate 3, and a theoretical model for selectivity is proposed.

Original languageEnglish (US)
Pages (from-to)283-297
Number of pages15
JournalNucleosides, Nucleotides and Nucleic Acids
Volume22
Issue number3
DOIs
StatePublished - Jun 16 2003

Fingerprint

Reverse Transcriptase Inhibitors
Conformations
Nucleotides
Nucleic Acid Synthesis Inhibitors
Sugars
RNA-Directed DNA Polymerase
Hand Strength
Enzymes
Nuclear magnetic resonance
Catalytic Domain
Molecular modeling
Theoretical Models
Phosphates
Human immunodeficiency virus 1 reverse transcriptase
triphosphoric acid
1,N(6)-ethenodeoxyadenosine
2'-deoxyadenosine triphosphate

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Genetics

Cite this

Conformational properties of nucleotide-based template-competitive HIV-1 reverse transcriptase inhibitors : Analysis of enzyme binding modes. / Lin, Weiying; Li, Ke; Moore, Bob; Doughty, Michael B.

In: Nucleosides, Nucleotides and Nucleic Acids, Vol. 22, No. 3, 16.06.2003, p. 283-297.

Research output: Contribution to journalArticle

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