A CONFORMATIONAL-ANALYSIS OF 3'-AZIDO-3'-DEOXYTHYMIDINE

An extensive conformational analysis of 3'-azido-3'-deoxythymidine (AZT) was performed at the semiempirical AM1 level with full relaxation of all geometric parameters and careful consideration of furan puckering and the rotational states of the thymine-furan, furan-azide, furan-methylene, and methylene-hydroxyl bonds. The search located 70 conformers, 21 of which have relative energies within 2.5 kcal/mol of the global minimum. Several geometric features, including various forms of hydrogen bonding, within this selected low-energy subset were examined in terms of their relative contributions to the conformational states of AZT. Hydrogen bonding of thymine's position 2 carbonyl oxygen atom to the hydroxymethyl group (O2-HO), which until recently has not been mentioned in the literature, is observed in a few low-energy AM1 conformations; however, this form is less favored at the AM1 level than the usually depicted modes involving the thymine moiety with the oxygen atoms of the hydroxyl and furan groups (H-6-OH and H-6-O(fur), as observed in the two crystallographically independent structures), as well as that involving the hydroxyl hydrogen and furan oxygen atoms (OH-O(fur), which also has not been mentioned for AZT in the literature until recently). The AM1-optimized geometries agree more closely with nuclear magnetic resonance data than with crystallographic structures and bear little resemblance to molecular mechanics results. The present study shows no evidence of a single dominant conformation or single structural parameter that determines AZT's conformational states. In contrast to our previous analogous study of cGMP, this computational study of AZT does not show strong evidence of a syn conformation with hydrogen bonding involving the base.