Conformational properties of nucleotide-based template-competitive HIV-1 reverse transcriptase inhibitors: analysis of enzyme binding modes.
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 (gamma). The major effect of the etheno group is to favor an extended, fully staggered anti conformation in the N1-C2-S-CH2 psi1 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'-deoxyadenosine 5'-triphosphate 3, and a theoretical model for selectivity is proposed.
Lin
Weiying
W
Department of Chemistry and Physics, Southeastern Louisiana University, Hammond, Louisiana 70402, USA.
Li
Ke
K
Moore
Bob M
BM
Doughty
Michael B
MB
D001667:Binding, Competitive; D003838:Deoxyadenine Nucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D003838:Deoxyadenine Nucleotides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C026600:2'-deoxyadenosine triphosphate