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

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.