Novel 3′-Spiro Nucleoside Analogues of TSAO-T. Part II. a Comparative Study Based on NMR Conformational Analysis in Solution and Theoretical Calculations

Abstract

The structures of two novel 3′-spiro nucleosides analogues of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-m 3 T, in solution, as derived from NMR spectroscopy are described. In these TSAO analogues the spiro amino oxathioledioxide moiety has been replaced by spiro amino oxazolone or spiro amino oxathiazoledioxide moieties. A comparative study based on theoretical calculations of the hydrophobicity, the solvation free energies and molecular electrostatic potentials (MEP) of the three compounds is also described. No significant conformational differences were detected in solution between TSAO-m 3 T and its analogues that might account for the differences observed in their inhibitory activity against HIV-1 RT. The calculated hydrophobicity (log P) values, dipole moments and the electrostatic contributions to the solvation free energies of the three spiro ring systems were also similar. However, the differences found in the calculated MEPs of the spiro systems between TSAO-m 3 T and its analogues suggest that the different electrostatic surroundings of the 4′′-amino group of the spiro moiety in the analogues may be responsible for a detrimental electrostatic interaction of the spiro rings with the Glu-B138 of RT.

Crystal Structure oftert-Butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in Complex with HIV-1 Reverse Transcriptase (RT) Redefines the Elastic Limits of the Non-nucleoside Inhibitor-Binding Pocket

“…Substitutions in the spiro ring (compounds 15 46 and 16 46 ) that alters/removes the above discussed H-bond and the water-mediated interactions with RT impair the potency of TSAO (Figure 3a, Table 4). In contrast, the removal of the amino group from the spiro ring (compound 17 15 ) causes only ~3-fold reduction in EC 50 .…”

TSAO Compounds: The Comprehensive Story of a Unique Family of HIV- 1 Specific Inhibitors of Reverse Transcriptase

“…From comparative NMR studies, no significant conformational differences were detected in solution between TSAO-m 3 T and these new spiro analogues that may account for the differences observed in their inhibitory activity against HIV-1 RT. Comparative studies based on theoretical calculations of the hydrophobicity, the solvation free energies and molecular electrostatic potentials (MEP) of the three spiro rings (aminooxathioledioxide, aminooxazolone and amino-1,2,3-oxathiazoledioxide) showed that the calculated hydrophobicity (log P) values, dipole moments and the electrostatic contributions to the solvation free energies of the three spiro ring systems were also similar [53]. However, the differences found in the calculated MEPs of the spiro systems between TSAO-m 3 T and its analogues suggest that the different electrostatic surroundings of the 4"-amino group of the spiro moiety in the analogues may be responsible for a detrimental electrostatic interaction of the spiro rings with the Glu-B138 of RT [53].…”

“…Comparative studies based on theoretical calculations of the hydrophobicity, the solvation free energies and molecular electrostatic potentials (MEP) of the three spiro rings (aminooxathioledioxide, aminooxazolone and amino-1,2,3-oxathiazoledioxide) showed that the calculated hydrophobicity (log P) values, dipole moments and the electrostatic contributions to the solvation free energies of the three spiro ring systems were also similar [53]. However, the differences found in the calculated MEPs of the spiro systems between TSAO-m 3 T and its analogues suggest that the different electrostatic surroundings of the 4"-amino group of the spiro moiety in the analogues may be responsible for a detrimental electrostatic interaction of the spiro rings with the Glu-B138 of RT [53]. Several sugar-modified 3'-spiro-TSAO derivatives including allofuranosyl-TSAO analogues [54], compounds bearing L-sugars [55] or with inverted configuration at the C-4' stereocenter [56] were also prepared.…”

“…(10)" in such a way that the strong dipole moment of the spiro group (µ = 8.4 debye) [53] is properly aligned in the field created by the positive electrostatic region emanating from Lys101 and Lys103 in the p66 subunit and the negatively charged Glu138 in the p51 subunit. This Glu138 is at hydrogen bond distance of the 4"-amino of the spiro group of TSAO-m 3 T. An additional polar interaction (hydrogen bond) is formed between the O4 of the thymine ring and the hydroxyl group of Thr139 in the p51 subunit (which explains why removal of this O4 is detrimental to activity).…”

TSAO Derivatives, Inhibitors of HIV-1 Reverse Transcriptase Dimerization: Recent Progress

“…Computational docking studies have found it necessary to expand the putative binding region beyond the NNRTI binding pocket and have led us to propose a binding mode distinct from that of "classical" NNRTIs [55]. TSAO-m 3 T (2) is shown to be a relatively hydrophobic ligand [58] with severely reduced flexibility whose conformation is preshaped to the geometry of its putative binding site, which is proposed to be at the interface between the p66 and p51 subunits of HIV-1 RT. The model points to a well defined part of the dimerization interface as a novel target for inhibitor design ( Fig.…”