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On the implications of the structure of 3′‐azido‐3′‐deoxythymidine and related compounds to antiviral activity
Author(s) -
Da Motta Neto Joaquim Delphino,
Zerner Michael C.,
De Alencastro Ricardo Bicca
Publication year - 1992
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560440506
Subject(s) - conformational isomerism , chemistry , steric effects , computational chemistry , pseudorotation , stereochemistry , degenerate energy levels , dipole , diad , crystallography , molecule , organic chemistry , physics , quantum mechanics , copolymer , polymer
We report structure–activity relation studies on 3′‐azido‐3′‐deoxythymidine (AZT) and the implications to the biological activity of this class of compounds. The adiabatic potential surface ( APS ) of the title compound has been examined with the LCAO – MO – SCF method within the AMI approximation. This study has shown at least 13 minima, all separated by small energy differences and barriers. We have found that the equilibrium favors the anti , gg conformations, in variance to previous studies that predicted the syn , gg conformers to be the most stable forms. The most stable conformation (A) is favored by about 0.5 kcal/mol. However, calculations simulating a bulk‐water environment suggest that the three lowest energy conformations (A, B, and C) become almost degenerate in solution. We suggest that the crystallographic conformation (L), characterized by a high dipole moment, and analogous to C, undergoes a strong stabilization upon rotation of the 3′‐azido group and that these two conformers, C and L, are the only ones in which the hydroxyl proton is free of steric hindrance. This last point has some relevance from the biological point of view since it is generally accepted that this site must be phosphorylated in order for AZT to achieve its therapeutic effects. The above results suggest that, once in solution, conformer L isomerizes to C, which is the bioactive form of AZT. © 1992 John Wiley & Sons, Inc.